July 16, 2025 • 38 mins
Polycystic kidney disease (PKD) is the most common inherited kidney disease. Those with PKD have a 50% chance of passing it on to their children and have progressively worse kidney function as they age. World-known PKD researcher Dr. Fouad Chebib joins Dr. Michael Koren to discuss the symptoms, risks, genetic cause, and treatment options for PKD. They also get into some new treatment methods being explored in clinical trials and what the future of PKD treatment may look like.
Dr. Chebib leads the Polycystic Kidney Disease Foundation Center of Excellence and the Discovery and Translational PKD Research Laboratory at the Mayo Clinic, Florida.
The Mayo Clinic Polycystic Kidney Disease (PKD) Resource Center includes many articles by Dr. Chebib himself.
Be a part of advancing science by participating in clinical research.
Have a question for Dr. Koren? Email him at askDrKoren@MedEvidence.com
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Announcement (00:00):
Welcome to MedEvidence, where we help you
navigate the truth behindmedical research with unbiased,
evidence-proven facts .Hosted bycardiologist and top medical
researcher, Dr.
Michael Koren.
Dr. Michael Koren (00:11):
Hello, I'm Dr .
Michael Koren, executive Editorof MedEvidence, and I have the
great privilege this morning ofspeaking with a world expert.
I have Dr.
Fouad Chebib here, who is aworld expert on polycystic
kidney disease, and I'm reallyexcited about this discussion,
Fouad, to talk about how you gotto this point, what motivated
(00:33):
you, and then break downpolycystic kidney disease for
the listeners and viewers ofMedEvidence! So welcome to
MedEvidence, thank you.
Dr. Fouad Chebib (00:41):
Thank you, Michael, for having me.
It's a great pleasure.
Dr. Michael Koren (00:43):
And this is fabulous.
So just start us off.
Tell us about how you got tothis point.
Tell us a little bit about howyou grew up, why you became a
doctor and, ultimately, how yougot really interested in
polycystic kidney disease, orPKD We'll use that term.
Dr. Fouad Chebib (00:58):
Yeah Well, thank you again for having me.
I mean, every doctor has theirown journey, why they picked
medicine, why they picked acertain specialty, and mine
might be a little bit unique,but also it's not.
You probably have heard a lotof stories you know family
history of inspiring ourphysicians to go into their path
(01:19):
, but I grew up in Lebanon, asmall country on the
Mediterranean Sea.
I always wanted to help people,whether through curing something
.
Always, as a child, I was veryintrigued in curing cancer,
curing HIV, curing diseases, andI didn't know.
I mean, I knew I want to be adoctor, but I didn't know I'm
(01:42):
going to become a nephrologistor a PKD specialist.
Dr. Michael Koren (01:44):
Other physicians in the family?
Dr. Fouad Chebib (01:45):
No other physicians in the family.
No other physicians in thefamily.
My father is in the flowerbusiness, and then wedding
events and what have you.
So I grew up doing these in thesummertime
Dr. Michael Koren (01:55):
-so you're paving your own path.
Dr. Fouad Chebib (01:56):
Yes, yes.
And then you know, one day Iwas in high school, my dad came
and sat next to me and my sisterand said I'm about to go on
dialysis.
So it was a very sudden eventfor the whole family.
He was not sick before and hestarted becoming uremic, which
means kind of buildup of thekidney toxins.
(02:16):
So it kind of shaped our wholeworld.
And then going into that, whenhe started dialysis, starting
going to see him in the dialysisunit and seeing how tough it
was, he had to kind of continuehis work and persevere despite
all these challenges.
And then understanding morethat it was due to polycystic
(02:37):
kidney disease.
He was the first in the family.
So there's about 5% of ourpatients who have what we call
de novo or new mutation, with noother family members.
So it came kind of really as ashock news and so I decided okay
, my dad went through a lot oftrouble through this, I want to
(02:58):
fix it.
And the first thing I kind ofat the time there was yahoo.
com.
So you look, there was noGoogle back then and Mayo Clinic
was kind of the go-to place tokind of figure out PKD.
And so I said, you know, I was17 or 18.
So I'm going to become anephrologist, I'm going to come
(03:18):
to Mayo to get the expertise andfix PKD,
Dr. Michael Koren (03:21):
-a nd that's what you did!
Dr. Fouad Chebib (03:22):
and that's what I did.
Dr. Michael Koren (03:23):
I love it.
Dr. Fouad Chebib (03:24):
Yes, it took a little bit, a few turns.
So I tried to come to the USfor med school, but it was very
tough for international studentsto come in.
It still is, I think.
So I did my med school back inLebanon.
Then I tried to get right awayto Mayo Clinic, but also it was
very tough not having thatexpertise to come first.
(03:46):
So I came to Boston.
I did research for two years ina molecular biology lab.
Dr. Michael Koren (03:53):
Which institute was that?
Dr. Fouad Chebib (03:54):
So it was at Beth Israel Deaconess, Harvard
Medical School.
Dr. Michael Koren (03:57):
That's where I did some of my training.
Dr. Fouad Chebib (03:59):
Yes.
So great place, still missBoston.
I stayed there for my internmedicine training at St
Elizabeth's with TuftsUniversity program.
Then I got the chance finallyto get to Mayo Clinic.
So I trained as a nephrologistin Mayo Clinic, Rochester.
I stayed on on staff to developmy PKD expertise and then three
(04:21):
years ago we moved down toJacksonville to the Mayo Clinic,
Florida campus.
Dr. Michael Koren (04:25):
Wow, great journey, great journey.
Dr. Fouad Chebib (04:27):
Yes, thank you .
Dr. Michael Koren (04:28):
So that's fabulous and inspiring.
So thank you for that.
So you're exactly where youthought you would be in high
school, which very few peoplecan say.
So it says something about youas a person that you set a plan
and you go after it and you getit.
So that's terrific, and I thinkthat speaks also to why you've
been so successful as now aworld-known PKD researcher.
(04:50):
So let's break down PKD for ouraudience.
I think obviously people have asense what kidney disease is,
but probably not a good sensefor disease.
So one polycystic kidneydisease.
Tell us about the incidence ofit, the genetics of it and also
a little bit about how referralpatterns work.
So go ahead.
Dr. Fouad Chebib (05:17):
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 abean.
You have two of those.
They filter the bloodcontinuously throughout the day,
regulate the electrolytes, thefluids, the blood pressure, lots
of hormones produced by thekidney, a lot of great function
of the kidney and you nevernotice that until the kidney
(05:39):
function goes down.
Now, with polycystic kidneydisease, instead of the size of
a fist, our patients are bornwith hundreds of these cysts on
each kidney, so hundreds ofthese very small fluid filled
sacs.
And then with time, as theygrow in age, in their teenage
and early adulthood, these cystsgrow and the kidney grows to
become almost the size of afootball.
(06:01):
So big, big size.
It takes big volume.
It can cause a lot of symptomsalso a lot of weight and pain
and what have you.
Also, these cysts can have manycomplications which we will
talk about.
So it's an inherited disease.
The majority of the patientswould know someone else in the
family who had PKD.
So they understand kind of thatjourney where patients, when
(06:24):
they're diagnosed, they kind ofunderstand that in the next few
years or depending on when theyget diagnosed.
Kidney failure is in thehorizon.
So it's very unique, also as amedical disease in general, that
you get the diagnosis and thennothing happens until 10, 20, 30
years later.
So also it has its own uniqueburden on the patients
Dr. Michael Koren (06:45):
-now in the genetics.
Just to interrupt for a second.
Is it autosomal, dominant,recessive, or are there
different types?
Dr. Fouad Chebib (06:51):
Yes, absolutely so.
In genetics world we dividethose into different patterns of
inheritance.
The common polycystic kidneydisease that we always refer to
as PKD is the ADPKD or autosomaldominant polycystic kidney
disease, which means that youonly need the change in the DNA
in one copy of the genes.
So we always inherit one copyfrom each parent.
(07:12):
So if one of the parents hasPKD, there's 50% chance that
this parent would pass on thatcopy to the child.
So each child would have 50%chance of having autosomal
dominant polycystic kidneydisease and if they inherit that
copy they will definitely getthe disease.
So it's what we call fullypenetrant.
There's other types of PKDautosomal recessive which where
(07:36):
the parents don't have thedisease, they just carry the
gene changes and then 25% chancefor each child to have that.
Typically it's a childhooddisease.
Unfortunately our youngchildren with ARPKD.
They end up being on dialysisearly on.
Dr. Michael Koren (07:53):
And has a breakdown between the autosomal
dominant version and theautosomal recessive version.
Dr. Fouad Chebib (07:59):
So the ADPKD is the most common inherited
kidney disease.
We think one in a thousand ofour population might have
polycystic ADPKD, as compared toARPKD, which is rarer one in
20,000.
So let's say in the US 350million, so 350,000 patients
with ADPKD.
Dr. Michael Koren (08:20):
-so it's still it's a number.
Dr. Fouad Chebib (08:22):
Yes, so it's the most common inherited kidney
and even if you compile all theother rare diseases, it might
be as common as all the othercommon diseases that we a lot of
people know about, like cysticfibrosis and other things.
So one in a thousand.
Some other studies may be alittle bit less, but that's
usually the typical.
Dr. Michael Koren (08:42):
So focusing on the autosomal dominant
version, which is the mostcommon version, give us a little
sense for how prognosis works.
Dr. Fouad Chebib (08:50):
Yeah.
So with ADPKD again, a lot oftimes we don't have these
symptoms.
So patients usually grow.
They don't know that they haveADPKD Very rarely.
They have very early onsetdisease where they start getting
a lot of symptoms, where thesecysts either burst and they see
a lot of blood, so what we callgross hematuria, or they have
(09:13):
cyst infection.
The typical is patients grow inage, they start having high
blood pressure.
Then their physician look attheir family history and they
say, oh yeah, my parent has PKDor got on dialysis.
Then they do a kidneyultrasound so they get screened
for PKD and they end up havingthe diagnosis and the typical
(09:34):
trajectory is kidney functionremains normal for the most part
until the 20s and 30s and thenlater on it starts declining
year after year and it dependson the severity.
So in terms of prognosis it'sconsidered a relatively good
prognosis in general.
If we take the big picture,we've done studies in Mayo
(09:57):
Clinic Rochester where we lookedat all PKD patients and the
general population in Minnesotaand the survival was the same
between the two groups.
So meaning our ADPKD patientsIf they have healthcare and they
take good care of themselves,they should live normal life.
However they would be expected.
The majority of the patientswould be expected to have kidney
(10:17):
failure.
So that does not happenregularly at the same time for
all the patients and even withinthe same family there can be
some variability, so it's aspectrum.
We think that patients mightreach kidney failure in their
30s up till their 80s, and thenthere's a small group that they
will never reach kidney failure.
They might have some chronickidney disease but not kidney
(10:38):
failure.
Dr. Michael Koren (10:39):
If the history runs its natural course,
people will eventually get ondialysis somewhere between 30
and 80, with 50s being typicalfor most people.
Dr. Fouad Chebib (10:49):
Yeah, so half of our patients would reach
kidney failure by age 60.
That can vary between thecohorts, between the US, europe,
other places, but if you reachto 60 and you haven't reached
kidney failure, you're betterthan half of ADPKD patients.
Dr. Michael Koren (11:05):
-and obviously dialysis is something
we do to take over the filteringfunction of the kidneys.
How about the other functionsof the kidneys?
Are they affected by PKD andhow do you have to deal with
that?
Dr. Fouad Chebib (11:15):
Yeah, so early on.
Again, the high blood pressureis controlled by the kidney, but
also these proteins are in theblood vessel.
So blood pressure can be higheven if the kidney function is
normal and even if the kidneysare not that enlarged.
Then later on that creatininenumber, the blood test, starts
rising, which tells us that theGFR, the kidney function, is
declining.
And if the kidney function goesdown to the 8% to 10% or
(11:39):
milliliter per minute, then weneed to replace the kidney
function through dialysis andpreferably through a preemptive
kidney transplant and preferablyto delay this as much as we can
.
And that's kind of the focus ofour research.
We'll talk a lot about how wecan push someone who was
supposed to get kidney failurein their 40s like my dad, early
40s how can we give them maybefive more years, maybe 10 more
(12:02):
years on their kidneys and haveall these milestones in life
which is huge not to be ondialysis or needing
transplantation.
Dr. Michael Koren (12:08):
Right and other types of complications of
kidney disease in general areanemia, for example?
Yes, is that relevant for PKDpatients?
Dr. Fouad Chebib (12:18):
Yeah, like any other chronic kidney disease
patients as their kidneyfunction goes down, these other
functions of the kidney, so notonly the electrolytes and the
potassium being filtered and thewater and the blood pressure,
but also there's other hormonesthat regulate the red blood
cells.
So there's anemia.
That kind of occurs at advancedstages of chronic kidney
(12:40):
disease and that occurs same asin PKD.
So in these situations we needto make sure that you have the
iron stores and then theypotentially we need to give them
injections under the skin toreplace the stimulating hormone
to kind of stimulate the bonemarrow to produce red cells.
And the other function isregulating the parathyroid
(13:00):
hormone, which also helps usregulate the calcium, phosphorus
and the bone health.
And that's also theresponsibility of the kidney.
So definitely a lot on theshoulders 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 atthis stage?
We'll get into some of theresearch 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 byinternational guidelines.
We got our first guidelines inPKD just this January 2025.
So there's a kind of what wecall basic optimized management
and we define this as makingsure that you're the healthiest
possible to slow your diseaseprocess as much as you can.
(13:49):
So that entails keeping yourblood pressure under very, very
good control, maybe much tighterthan the general population.
So we give numbers like 110mmHg, over 75 for those who we
would think they would advancefaster.
(14:09):
We want them to hydrate a lotbecause vasopressin or the
thirst hormone stimulates thesekidney cysts to grow.
So we want them to hydrate very, very well, meaning kind of 3
to 3.5 liters, so like 100ounces of fluids throughout the
day.
We want them to cut the salt intheir diet because that's not
only helps us with bloodpressure control but helps us
suppress the vasopressin or thethirst hormone much easier with
(14:32):
less water.
And then we want them not togain weight.
So body mass index is key tokeep it on the normal level.
There's a lot of studiesshowing that if we gain weight,
our cysts are gonna grow faster,our kidney function is gonna
decline faster.
And then we look at all theother things that come with
chronic kidney disease.
So that's for all the patients.
(14:54):
Now there's about two-thirds ofthe patients.
We think they're gonna reachkidney failure by age 60.
And that's defined byguidelines and by us that these
patients are at risk of rapidprogression, which means, again,
they're at risk of needingdialysis or transplantation by
age 60.
We're now trying to push totreat more patients who reach
(15:17):
even by 65, because we think youneed to push even longer for
these patients.
So in these situations there'san FDA approved treatment that
has been approved since 2018.
It's called Tolvaptan orJynarque.
It blocks the effect ofvasopressin, that thirst hormone
.
So this medication goes andblocks that receptor and then
(15:41):
studies years over years haveshown that it slows the disease
progression.
Dr. Michael Koren (15:45):
Yeah, and just an aside, we did some of
that work here in NortheastFlorida.
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 pavedthe way hopefully now for many,
many new other treatments.
Now this treatment that'sapproved, not all the patients
are eligible for it in terms ofrisk and benefit.
It does come with risks,especially with the liver
enzymes.
We have to check those on amonthly basis for the first year
(16:11):
and a half and then every threemonths.
Then also the patients aregonna, because we're blocking
the effect of the thirst.
Then the kidney thinks it needsto make a lot of urine.
So our patients are gonna makefive to six liters of urine and
then our patients have to keepdrinking the fluid, the same
amount of fluids or even more.
So that comes with kind of whatwe call on target effect.
(16:32):
But for patients, they feel itas a side effect that they're
very thirsty, they're drinkingtons of fluids, they're going to
the bathroom a lot.
However, a lot of patientstolerate that, adapt to that and
they see a lot of benefit.
But not all the patients areable to tolerate it.
So now we need definitely moretreatments 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 triggersa number of questions in my
mind.
So you mentioned aboutpotentially diagnosing people at
a younger age and obviously,because it's a genetic illness,
you could screen offspring ofpeople.
Is there any advantage to that?
Is it important to know that afive-year-old has the disease,
(17:14):
and how do you change theircourse 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 wecan do, in a sense that there's
no big clinical trials that cango they can go to, at least not
yet, and then there's no FDAapproved treatment for patients
who are not adults.
So for younger patients we sayto the family establish a
(17:39):
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'sreally necessary.
Make sure they don't gainweight, they don't smoke, so all
these things are important tobecome a habit and natural habit
for them.
And then also we advise them totell their pediatrician that
(18:01):
there's a family history of PKD.
So then their blood pressure ischecked very carefully and if
there is high blood pressure,which could be the case, then
just treat it as such and thenwait until they're an adult age,
then discuss when it's theright time to be screened and
get diagnosed.
But definitely for our patientswho are 18 and above or
(18:22):
individuals at risk.
So anyone who has familyhistory of ADPKD and there are
18 or above they should starttalking about.
Okay, should I go get screened?
" Talk to my doctor, get thekidney ultrasound and the only
caveat to getting screened earlyis there might be a risk of not
getting a life insurance.
So they need to kind ofconsider that and then either
(18:42):
get a life insurance beforegoing and getting screened.
But the earlier the diagnosis,the earlier we start treatment,
the earlier they're proactiveabout their health, the more
benefit they're gonna have.
But it's definitely there's nokind of one answer for everybody
, because some of our youngerfolks they need to go through
college and they need to passthrough some milestones in life
(19:06):
before they get this bigdiagnosis, so it's very
different for each of them.
Dr. Michael Koren (19:09):
It's a heavy burden psychologically.
Yeah understood.
So you mentioned the vasopressinantagonists and we'll call them
Vaptans to make it easy.
I know there was a number ofthem that are being studied.
Are there others on the marketnow 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 othertypes of Vaptans.
There was one that was about togo into larger clinical trials
but they stopped doing that.
The main kind of benefit ofthese other Vaptans is trying to
see if they don't affect theliver and so there's less need
(19:47):
to do all these monitoring, soless burden on the patients.
But all the Vaptans will havethe same effect of drinking a
lot of fluids because that's howthey work.
So there's potentially otherformulations, maybe longer
acting, maybe there's othertypes of Vap tans.
For example there's a study onsnake venom that can cause, that
(20:08):
, 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.
But they're still very early in.
Dr. Michael Koren (20:17):
And are there any other classes of drugs that
are specifically approved fortreating polycystic kidney
disease?
Dr. Fouad Chebib (20:23):
So other than blood pressure control, which we
favor, the first line is ACEinhibitors or ARB.
Those are kind of the firstclass types of blood pressure
medications.
The only FDA approved treatmentis tolvaptine, and the others
are still in clinical trial.
Dr. Michael Koren (20:39):
So the classes of blood pressure
medicines that you mentionedultimately block a hormone
called angiotensin II and thathas specific effects on the
cysts, or just general good forreducing proteinuria and things
like that.
Dr. Fouad Chebib (20:52):
Yeah, so with PKD we expect very little bit of
proteinuria, so less than onegram, but the main effect is.
So there has been a lot ofhypothesis, a lot of studies,
that blocking the pathway of theangiotensin pathway could slow
the disease progression and thatled to a very large study
within the US called HALT PKD,H-A-L-T, P-K-D and trying to
(21:19):
look at giving two types, so theACE inhibitors and the ARV
together, and also targetingmuch lower blood pressure target
.
So one arm was 110 over 75 orless, actually between 95 to 110
, and then the other was the 120130 and the study was called
negative but the p-value was0.05.
Okay, and what was significantis that in the group that was
(21:42):
treated much aggressively on theblood pressure target of 110
over 75, the kidney volumes orthe cysts grew a little bit less
faster, so 6% versus 5%.
It was significantstatistically and that's where
the recommendation now from PKDgoes for patients who are
younger and at risk of rapidprogression, let's target 110
(22:03):
over 75.
Dr. Michael Koren (22:04):
Got it.
So just for the lay audienceout there.
We got a little technical therewith p-values and things, but
it was a borderline study.
But the gestalt is that there'sprobably some value to go lower
and use the class of drug thatblocks 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 intrials.
It's still a good idea to keepthe blood pressure lower for
these patients, as long as theytolerate it.
Dr. Michael Koren (22:33):
Got it.
You mentioned a little bit ofdietary things.
Any other words of wisdom forpeople in terms of how strict
they need to be with their dietif they have PKD problems?
Dr. Fouad Chebib (22:44):
Yeah, there's a lot of interest from our
patients and from the scientificcommunity on interventions on
diet.
Now it's very interesting forPKD we think it's a metabolic
type of disease, so there'sissues with the mitochondria,
the powerhouse of the cell,where in PKD that's affected,
and so we think that if we dosome interventions on the diet
(23:07):
we can reprogram how the kidneycells 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 onketogenic diet, on giving some
either medical food or othercompounds to kind of reprogram
(23:31):
the mitochondria.
So all these are still inclinical trials.
There's a lot of studies underwhat we call preclinical, so
animal models who have PKD.
They were given theseinterventions, either
restricting calories or doketogenic diet or do some
beta-hydroxybutyrate, which iskind of the ketogenic form that
(23:52):
is given as a supplement.
So all these were positive inanimal models.
There's not a lot of big trialsin humans.
So we came up actually withwhat we call the PKD diet and we
said there's a lot of evidencethat if you're overweight your
disease is gonna progress faster.
So let's bring down that weight.
And the most efficient way, orthe safest way that is now for
(24:16):
other weight loss, is to docaloric restriction.
And even if you cut down by 10to 20% of your calories and keep
your body mass index close tothat 20 to 25 range, then you're
probably gonna gain a lot ofbenefit years.
The other restrictions become.
We don't like to restrictprotein unless the kidney
function is low, so that'ssomething 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 restrictingprotein, 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 isabove 30 milliliter per minute
or for patients they think it's30, or they know about it as 30%
then we could go.
.
.
we don't have to restrict toomuch.
So 0.8 gram per kilogram ofprotein up to 1.3 gram per
kilogram per day If their kidneyfunction is less than 30, then
we start doing some morerestrictions.
If they're on dialysis, it'scompletely opposite.
(25:09):
We want them to be on becausethey get malnourished and they
lose a lot of the energy and theprotein.
We want them to be on heavyprotein.
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 theystart seeing a lot of these
restrictions, is to talk to aPKD dietician or a renal
nephrology dietician and theycan guide them through these
other restrictions.
And as the kidney function goeslow, we restrict potassium,
phosphorus, other things, butsodium.
Water weight is kind of keyearly on in life.
Dr. Michael Koren (25:41):
Right.
So we're both research peopleand we like to look at the
future.
We perceive that part of ourrole as physicians is not only
to do what's known today, but tofigure out what to do for
tomorrow.
So give us a little insightinto what people are thinking
about in terms of what we'regoing to do tomorrow for people
that have PKD.
Dr. Fouad Chebib (26:02):
Yes.
So it's very, very exciting inPKD in 2025, 2026, because all
the scientific advances thathappened over the 10 to 20 years
, mostly over the last five to10 years, has now culminated
into things that we could starttesting in humans, not only kind
(26:24):
of talk about it in the papersand in animal models, right.
So all this kind of work nowit's almost at the same time
coming together.
There's also interest fromindustry or pharmaceutical
company where they did a lot ofthe research and development.
They took all the otheracademic scientific work and
moved it on to potential newtreatments, and so definitely
(26:48):
there's a big unmet need.
There's a big gap in takingcare of our patients because,
yes, we talk about how we keepthem healthy, but we haven't
talked about how to completelyprevent kidney failure.
So completely preventing kidneyfailure, that's my lifetime
goal.
Dream is when patients come tome I'm like, okay, we're gonna
do this, this and this and youdon't have to worry about
(27:10):
dialysis, transplant.
We're not there yet.
I keep promising my patientsand our community.
Five to eight years maybe iskind of my goal, and by that we
talk about gene therapy, aboutcures, and that's gonna happen.
We have a lot of initiatives.
At Mayo Clinic Florida, forexample, we have now an organ
perfusion studies unit that Ico-direct and we're working on
(27:31):
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 whatwe call cold perfusion.
So there's just kind of a pumpthat 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 kidneysto kind of not be as happy and
then it goes into the recipient,the patient who needs that
(28:03):
organ transplant, and usuallythat kidney doesn't work well
right away.
It takes some time, so there'ssome injury or kind of issues
that happen with the tubules ofthese kidneys.
So what we're trying to createis to perfuse the kidneys or
livers and keep themmetabolically and
physiologically active.
So we want to keep thesekidneys that we take out, that
(28:26):
were not good enough to go andget transplanted in a patient,
put them in our perfusion system.
That's warm perfusion with newliquid new fluids and a system
that keeps that kidney makingeven urine for almost three days
and by doing that it becomes aplatform to test gene therapy or
(28:47):
other rejuvenating, anti-agingkind of processes.
Doing the same for the liverfor two weeks for the liver.
Dr. Michael Koren (28:54):
So there's thoughts that we can eventually
fix the gene that's responsiblefor the problem.
Dr. Fouad Chebib (28:59):
Yes, so, as you know, with gene therapy now
it became also extremelyadvanced over the past 10 years.
You know you can go in and justkind of edit one change in the
DNA and there is a lot oftherapies that are now well,
there's FDA approved therapiesfor gene therapy.
The kidney is quite challenging, so one is, the kidney protects
(29:23):
itself.
So it's very hard, verychallenging to get these vectors
, whether it's a virus orsomething non-viral vectors, to
go and deliver these tools tofix the kidney, the cells.
So the first thing is how can weget it to the kidney?
And then how can we get it tothe right place in the kidney,
and then what is within thepackage, what should go into the
(29:45):
kidney?
So these three things if wekind of overcome and I think
technology is helping us how todeliver directly to the kidney,
there's kind of almost like abypass on the kidney.
Uh, you know, while the kidneyis still in the body we can
perfuse it for two hours notaffecting the other organs
interesting and deliver this.
There's a lot of advance on thevectors, on how to deliver and
(30:07):
then understanding the genetics.
Now there's also more advanceson what should go in and get
fixed.
Like what is that tool?
So hopefully, with liningeverything together, that's kind
of my dream is to start doingthese procedures where patients
come in early, even at youngerage, at 12, 15, will go in, fix
(30:28):
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 eightyears 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,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 dowith growth factors.
Just briefly mention that orany others that look
particularly promising in sortof the short to intermediate
term.
Dr. Fouad Chebib (30:59):
Yes, absolutely.
So before we reach the stars westill have some relatively low
hanging fruits.
So in any disease we wanna slowit down if we cannot completely
prevent it.
So we don't want the perfect tobe the enemy of very good.
So the very good that's now inthe next three to five years
it's going into clinical trialsand there's a lot of science and
(31:20):
great science actually behindit.
So there's multiple things thatare now ongoing.
So you know, think about thesekidney cysts.
So in addition to that,vasopressin or the thirst is
stimulating the fluid secretion.
Also, these cells are kind ofproliferating or they're kind of
doubling up with time.
So then you can create thisstructure right.
(31:43):
It's almost like a benign, mass, benign tumor.
It's growing, it's fillingfluids but also it's growing in
size.
So if we can find somethingthat's tolerated, that's almost
like stops the proliferation orthe growth of these kidney, it
would be perfect, right?
So with studies actually done atMayo Clinic, Florida with Dr.
(32:05):
Eduardo Chini, he found out hewas working, he's actually a
scientist, a physician, and ascientist works on anti-aging
processes and he found throughthe anti-aging process that
there's a growth factor that ifyou target it you stop PKD from
growing.
So if you create, for example,an antibody that prevents the
(32:29):
cleavage or the, so let's kindof step back.
So you have kind of a growthfactor, you have a receptor.
That receptor, if it getsstimulated, the kidney is being
stimulated, so it's InsulinGrowth Factor Receptor.
Now for that to be stimulatedit kind of comes as like a key
and like a two pieces, and ifthose two pieces are still
(32:52):
together then you cannotstimulate the growth factor.
So naturally there's somethingthat comes and breaks them apart
and then it stimulates thegrowth 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 kindof opening up and then there's
no more growth factor free to bestimulated, 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 totreating PKD may be coming to a
clinical trial center near youin 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 wehave a lot of options.
Again, some patients don'ttolerate Tolvaptine.
They cannot be on Tolvaptinebecause they have work.
They cannot be in bathroombreaks every so often, so that
gives them a lot of options andthere's a lot of studies behind
this and we hope that it's safe.
(33:56):
We think it's safe.
Dr. Michael Koren (33:58):
Any other approaches other than the growth
factor approach that peopleshould know about?
Dr. Fouad Chebib (34:02):
Yeah.
So there's other kind ofapproaches as well.
So there's what we callanti-microRNA.
So with PKD, again one copy isnot working, one copy of the
gene, so that DNA is defected.
So the protein that's supposedto be made out of that copy is
(34:23):
what we call less functional.
So there is less of thispolycystin, one protein or
polycystin two.
So these are the proteins thatif you have less of, then the
kidney starts making the kidneycyst.
So there's an approach whereyou know just also stepping back
.
So DNA goes to messenger RNA,then goes to protein.
So typically in a natural waythe cells are making these
(34:49):
messenger RNA and then they'redegrading them or they go away.
You make more and so forth.
There's a process where itcomes and particularly for the
PKD1 and polycystin1, it stopsthat messenger RNA from being
degraded.
So you keep kind of themachinery and the factory.
You overwork almost your otherparents.
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 moreof that protein Interesting.
That's the concept.
It went through the first phaseof phase 1B Interesting and
it's going into phase 3.
So that's one option.
And then there's another set oftreatments.
That's also very exciting, butit will only right now, for the
(35:42):
first part, it's gonna be onlyfor 10% of patients with
specific area where they havethe PKD1 mutation.
So PKD1 is one of the largestgenes in our body and it's a big
protein.
But if some of these mutationsor these changes in the DNA, the
protein, what happens is itgets misfolded and stuck in the
(36:04):
endoplasmic reticulum.
So almost like you make it inthe 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 unfoldit and then sent and patched it
up just to go there.
So there's, those are going tocome into trials also.
(36:26):
End of this year.
It's gonna be an oral medicationand it's only a small portion
of patients.
So again, a lot of excitement.
Not all these options are forall the patients.
So what's exciting to me inclinic is when I see our
patients, I give them the optionof the standard of care first.
This is what we need to do.
(36:46):
If you're eligible for tolvap,then let's try it.
If you don't feel this is theright thing, we definitely need
to go to clinical trial, andthat's how we advance, not only
for our patients but, also fortheir kids.
And that's the unique thingabout PKD they're always
motivated because not only forthem they want to fix this for
(37:07):
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 largestclinics in the country and it's
very exciting.
So we have a kind of processwhere our patients come in.
We have myself, our co-director, Dr.
Mao, and then two of our nursepractitioners and we follow
quite a large number.
Dr. Michael Koren (37:28):
Wow, Very nice.
Well, this has been afascinating discussion.
Thank you so much for sharingall your knowledge.
It's been amazing.
I've learned a tremendousamount and it looks like we're
on the precipice of a lot ofreally exciting things in this
space and I'm looking forward tobeing part of these advances
hopefully in the very, very nearfuture, but a lot of different
(37:53):
ways that we may be able toimpact 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 forshedding 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 stayat home.
There's a lot of things you cando 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 agreat researcher, and how to get
in touch with us in terms ofresearch opportunities
Absolutely researcher and how toget in touch with us in terms
of research opportunities,absolutely so.
Thank you again for being partof MedEvidence.
Thank you for having me.
Announcement (38:27):
Thanks for joining the MedEvidence podcast.
To learn more, head over toMedEvidence.
com or subscribe to our podcaston your favorite podcast
platform.
Welcome to MedEvidence, where we help you
navigate the truth behindmedical research with unbiased,
evidence-proven facts .Hosted bycardiologist and top medical
researcher, Dr.
Michael Koren.
Dr. Michael Koren (00:11):
Hello, I'm Dr .
Michael Koren, executive Editorof MedEvidence, and I have the
great privilege this morning ofspeaking with a world expert.
I have Dr.
Fouad Chebib here, who is aworld expert on polycystic
kidney disease, and I'm reallyexcited about this discussion,
Fouad, to talk about how you gotto this point, what motivated
(00:33):
you, and then break downpolycystic kidney disease for
the listeners and viewers ofMedEvidence! So welcome to
MedEvidence, thank you.
Dr. Fouad Chebib (00:41):
Thank you, Michael, for having me.
It's a great pleasure.
Dr. Michael Koren (00:43):
And this is fabulous.
So just start us off.
Tell us about how you got tothis point.
Tell us a little bit about howyou grew up, why you became a
doctor and, ultimately, how yougot really interested in
polycystic kidney disease, orPKD We'll use that term.
Dr. Fouad Chebib (00:58):
Yeah Well, thank you again for having me.
I mean, every doctor has theirown journey, why they picked
medicine, why they picked acertain specialty, and mine
might be a little bit unique,but also it's not.
You probably have heard a lotof stories you know family
history of inspiring ourphysicians to go into their path
(01:19):
, but I grew up in Lebanon, asmall country on the
Mediterranean Sea.
I always wanted to help people,whether through curing something
.
Always, as a child, I was veryintrigued in curing cancer,
curing HIV, curing diseases, andI didn't know.
I mean, I knew I want to be adoctor, but I didn't know I'm
(01:42):
going to become a nephrologistor a PKD specialist.
Dr. Michael Koren (01:44):
Other physicians in the family?
Dr. Fouad Chebib (01:45):
No other physicians in the family.
No other physicians in thefamily.
My father is in the flowerbusiness, and then wedding
events and what have you.
So I grew up doing these in thesummertime
Dr. Michael Koren (01:55):
-so you're paving your own path.
Dr. Fouad Chebib (01:56):
Yes, yes.
And then you know, one day Iwas in high school, my dad came
and sat next to me and my sisterand said I'm about to go on
dialysis.
So it was a very sudden eventfor the whole family.
He was not sick before and hestarted becoming uremic, which
means kind of buildup of thekidney toxins.
(02:16):
So it kind of shaped our wholeworld.
And then going into that, whenhe started dialysis, starting
going to see him in the dialysisunit and seeing how tough it
was, he had to kind of continuehis work and persevere despite
all these challenges.
And then understanding morethat it was due to polycystic
(02:37):
kidney disease.
He was the first in the family.
So there's about 5% of ourpatients who have what we call
de novo or new mutation, with noother family members.
So it came kind of really as ashock news and so I decided okay
, my dad went through a lot oftrouble through this, I want to
(02:58):
fix it.
And the first thing I kind ofat the time there was yahoo.
com.
So you look, there was noGoogle back then and Mayo Clinic
was kind of the go-to place tokind of figure out PKD.
And so I said, you know, I was17 or 18.
So I'm going to become anephrologist, I'm going to come
(03:18):
to Mayo to get the expertise andfix PKD,
Dr. Michael Koren (03:21):
-a nd that's what you did!
Dr. Fouad Chebib (03:22):
and that's what I did.
Dr. Michael Koren (03:23):
I love it.
Dr. Fouad Chebib (03:24):
Yes, it took a little bit, a few turns.
So I tried to come to the USfor med school, but it was very
tough for international studentsto come in.
It still is, I think.
So I did my med school back inLebanon.
Then I tried to get right awayto Mayo Clinic, but also it was
very tough not having thatexpertise to come first.
(03:46):
So I came to Boston.
I did research for two years ina molecular biology lab.
Dr. Michael Koren (03:53):
Which institute was that?
Dr. Fouad Chebib (03:54):
So it was at Beth Israel Deaconess, Harvard
Medical School.
Dr. Michael Koren (03:57):
That's where I did some of my training.
Dr. Fouad Chebib (03:59):
Yes.
So great place, still missBoston.
I stayed there for my internmedicine training at St
Elizabeth's with TuftsUniversity program.
Then I got the chance finallyto get to Mayo Clinic.
So I trained as a nephrologistin Mayo Clinic, Rochester.
I stayed on on staff to developmy PKD expertise and then three
(04:21):
years ago we moved down toJacksonville to the Mayo Clinic,
Florida campus.
Dr. Michael Koren (04:25):
Wow, great journey, great journey.
Dr. Fouad Chebib (04:27):
Yes, thank you .
Dr. Michael Koren (04:28):
So that's fabulous and inspiring.
So thank you for that.
So you're exactly where youthought you would be in high
school, which very few peoplecan say.
So it says something about youas a person that you set a plan
and you go after it and you getit.
So that's terrific, and I thinkthat speaks also to why you've
been so successful as now aworld-known PKD researcher.
(04:50):
So let's break down PKD for ouraudience.
I think obviously people have asense what kidney disease is,
but probably not a good sensefor disease.
So one polycystic kidneydisease.
Tell us about the incidence ofit, the genetics of it and also
a little bit about how referralpatterns work.
So go ahead.
Dr. Fouad Chebib (05:17):
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 abean.
You have two of those.
They filter the bloodcontinuously throughout the day,
regulate the electrolytes, thefluids, the blood pressure, lots
of hormones produced by thekidney, a lot of great function
of the kidney and you nevernotice that until the kidney
(05:39):
function goes down.
Now, with polycystic kidneydisease, instead of the size of
a fist, our patients are bornwith hundreds of these cysts on
each kidney, so hundreds ofthese very small fluid filled
sacs.
And then with time, as theygrow in age, in their teenage
and early adulthood, these cystsgrow and the kidney grows to
become almost the size of afootball.
(06:01):
So big, big size.
It takes big volume.
It can cause a lot of symptomsalso a lot of weight and pain
and what have you.
Also, these cysts can have manycomplications which we will
talk about.
So it's an inherited disease.
The majority of the patientswould know someone else in the
family who had PKD.
So they understand kind of thatjourney where patients, when
(06:24):
they're diagnosed, they kind ofunderstand that in the next few
years or depending on when theyget diagnosed.
Kidney failure is in thehorizon.
So it's very unique, also as amedical disease in general, that
you get the diagnosis and thennothing happens until 10, 20, 30
years later.
So also it has its own uniqueburden on the patients
Dr. Michael Koren (06:45):
-now in the genetics.
Just to interrupt for a second.
Is it autosomal, dominant,recessive, or are there
different types?
Dr. Fouad Chebib (06:51):
Yes, absolutely so.
In genetics world we dividethose into different patterns of
inheritance.
The common polycystic kidneydisease that we always refer to
as PKD is the ADPKD or autosomaldominant polycystic kidney
disease, which means that youonly need the change in the DNA
in one copy of the genes.
So we always inherit one copyfrom each parent.
(07:12):
So if one of the parents hasPKD, there's 50% chance that
this parent would pass on thatcopy to the child.
So each child would have 50%chance of having autosomal
dominant polycystic kidneydisease and if they inherit that
copy they will definitely getthe disease.
So it's what we call fullypenetrant.
There's other types of PKDautosomal recessive which where
(07:36):
the parents don't have thedisease, they just carry the
gene changes and then 25% chancefor each child to have that.
Typically it's a childhooddisease.
Unfortunately our youngchildren with ARPKD.
They end up being on dialysisearly on.
Dr. Michael Koren (07:53):
And has a breakdown between the autosomal
dominant version and theautosomal recessive version.
Dr. Fouad Chebib (07:59):
So the ADPKD is the most common inherited
kidney disease.
We think one in a thousand ofour population might have
polycystic ADPKD, as compared toARPKD, which is rarer one in
20,000.
So let's say in the US 350million, so 350,000 patients
with ADPKD.
Dr. Michael Koren (08:20):
-so it's still it's a number.
Dr. Fouad Chebib (08:22):
Yes, so it's the most common inherited kidney
and even if you compile all theother rare diseases, it might
be as common as all the othercommon diseases that we a lot of
people know about, like cysticfibrosis and other things.
So one in a thousand.
Some other studies may be alittle bit less, but that's
usually the typical.
Dr. Michael Koren (08:42):
So focusing on the autosomal dominant
version, which is the mostcommon version, give us a little
sense for how prognosis works.
Dr. Fouad Chebib (08:50):
Yeah.
So with ADPKD again, a lot oftimes we don't have these
symptoms.
So patients usually grow.
They don't know that they haveADPKD Very rarely.
They have very early onsetdisease where they start getting
a lot of symptoms, where thesecysts either burst and they see
a lot of blood, so what we callgross hematuria, or they have
(09:13):
cyst infection.
The typical is patients grow inage, they start having high
blood pressure.
Then their physician look attheir family history and they
say, oh yeah, my parent has PKDor got on dialysis.
Then they do a kidneyultrasound so they get screened
for PKD and they end up havingthe diagnosis and the typical
(09:34):
trajectory is kidney functionremains normal for the most part
until the 20s and 30s and thenlater on it starts declining
year after year and it dependson the severity.
So in terms of prognosis it'sconsidered a relatively good
prognosis in general.
If we take the big picture,we've done studies in Mayo
(09:57):
Clinic Rochester where we lookedat all PKD patients and the
general population in Minnesotaand the survival was the same
between the two groups.
So meaning our ADPKD patientsIf they have healthcare and they
take good care of themselves,they should live normal life.
However they would be expected.
The majority of the patientswould be expected to have kidney
(10:17):
failure.
So that does not happenregularly at the same time for
all the patients and even withinthe same family there can be
some variability, so it's aspectrum.
We think that patients mightreach kidney failure in their
30s up till their 80s, and thenthere's a small group that they
will never reach kidney failure.
They might have some chronickidney disease but not kidney
(10:38):
failure.
Dr. Michael Koren (10:39):
If the history runs its natural course,
people will eventually get ondialysis somewhere between 30
and 80, with 50s being typicalfor most people.
Dr. Fouad Chebib (10:49):
Yeah, so half of our patients would reach
kidney failure by age 60.
That can vary between thecohorts, between the US, europe,
other places, but if you reachto 60 and you haven't reached
kidney failure, you're betterthan half of ADPKD patients.
Dr. Michael Koren (11:05):
-and obviously dialysis is something
we do to take over the filteringfunction of the kidneys.
How about the other functionsof the kidneys?
Are they affected by PKD andhow do you have to deal with
that?
Dr. Fouad Chebib (11:15):
Yeah, so early on.
Again, the high blood pressureis controlled by the kidney, but
also these proteins are in theblood vessel.
So blood pressure can be higheven if the kidney function is
normal and even if the kidneysare not that enlarged.
Then later on that creatininenumber, the blood test, starts
rising, which tells us that theGFR, the kidney function, is
declining.
And if the kidney function goesdown to the 8% to 10% or
(11:39):
milliliter per minute, then weneed to replace the kidney
function through dialysis andpreferably through a preemptive
kidney transplant and preferablyto delay this as much as we can
.
And that's kind of the focus ofour research.
We'll talk a lot about how wecan push someone who was
supposed to get kidney failurein their 40s like my dad, early
40s how can we give them maybefive more years, maybe 10 more
(12:02):
years on their kidneys and haveall these milestones in life
which is huge not to be ondialysis or needing
transplantation.
Dr. Michael Koren (12:08):
Right and other types of complications of
kidney disease in general areanemia, for example?
Yes, is that relevant for PKDpatients?
Dr. Fouad Chebib (12:18):
Yeah, like any other chronic kidney disease
patients as their kidneyfunction goes down, these other
functions of the kidney, so notonly the electrolytes and the
potassium being filtered and thewater and the blood pressure,
but also there's other hormonesthat regulate the red blood
cells.
So there's anemia.
That kind of occurs at advancedstages of chronic kidney
(12:40):
disease and that occurs same asin PKD.
So in these situations we needto make sure that you have the
iron stores and then theypotentially we need to give them
injections under the skin toreplace the stimulating hormone
to kind of stimulate the bonemarrow to produce red cells.
And the other function isregulating the parathyroid
(13:00):
hormone, which also helps usregulate the calcium, phosphorus
and the bone health.
And that's also theresponsibility of the kidney.
So definitely a lot on theshoulders 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 atthis stage?
We'll get into some of theresearch 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 byinternational guidelines.
We got our first guidelines inPKD just this January 2025.
So there's a kind of what wecall basic optimized management
and we define this as makingsure that you're the healthiest
possible to slow your diseaseprocess as much as you can.
(13:49):
So that entails keeping yourblood pressure under very, very
good control, maybe much tighterthan the general population.
So we give numbers like 110mmHg, over 75 for those who we
would think they would advancefaster.
(14:09):
We want them to hydrate a lotbecause vasopressin or the
thirst hormone stimulates thesekidney cysts to grow.
So we want them to hydrate very, very well, meaning kind of 3
to 3.5 liters, so like 100ounces of fluids throughout the
day.
We want them to cut the salt intheir diet because that's not
only helps us with bloodpressure control but helps us
suppress the vasopressin or thethirst hormone much easier with
(14:32):
less water.
And then we want them not togain weight.
So body mass index is key tokeep it on the normal level.
There's a lot of studiesshowing that if we gain weight,
our cysts are gonna grow faster,our kidney function is gonna
decline faster.
And then we look at all theother things that come with
chronic kidney disease.
So that's for all the patients.
(14:54):
Now there's about two-thirds ofthe patients.
We think they're gonna reachkidney failure by age 60.
And that's defined byguidelines and by us that these
patients are at risk of rapidprogression, which means, again,
they're at risk of needingdialysis or transplantation by
age 60.
We're now trying to push totreat more patients who reach
(15:17):
even by 65, because we think youneed to push even longer for
these patients.
So in these situations there'san FDA approved treatment that
has been approved since 2018.
It's called Tolvaptan orJynarque.
It blocks the effect ofvasopressin, that thirst hormone
.
So this medication goes andblocks that receptor and then
(15:41):
studies years over years haveshown that it slows the disease
progression.
Dr. Michael Koren (15:45):
Yeah, and just an aside, we did some of
that work here in NortheastFlorida.
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 pavedthe way hopefully now for many,
many new other treatments.
Now this treatment that'sapproved, not all the patients
are eligible for it in terms ofrisk and benefit.
It does come with risks,especially with the liver
enzymes.
We have to check those on amonthly basis for the first year
(16:11):
and a half and then every threemonths.
Then also the patients aregonna, because we're blocking
the effect of the thirst.
Then the kidney thinks it needsto make a lot of urine.
So our patients are gonna makefive to six liters of urine and
then our patients have to keepdrinking the fluid, the same
amount of fluids or even more.
So that comes with kind of whatwe call on target effect.
(16:32):
But for patients, they feel itas a side effect that they're
very thirsty, they're drinkingtons of fluids, they're going to
the bathroom a lot.
However, a lot of patientstolerate that, adapt to that and
they see a lot of benefit.
But not all the patients areable to tolerate it.
So now we need definitely moretreatments 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 triggersa number of questions in my
mind.
So you mentioned aboutpotentially diagnosing people at
a younger age and obviously,because it's a genetic illness,
you could screen offspring ofpeople.
Is there any advantage to that?
Is it important to know that afive-year-old has the disease,
(17:14):
and how do you change theircourse 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 wecan do, in a sense that there's
no big clinical trials that cango they can go to, at least not
yet, and then there's no FDAapproved treatment for patients
who are not adults.
So for younger patients we sayto the family establish a
(17:39):
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'sreally necessary.
Make sure they don't gainweight, they don't smoke, so all
these things are important tobecome a habit and natural habit
for them.
And then also we advise them totell their pediatrician that
(18:01):
there's a family history of PKD.
So then their blood pressure ischecked very carefully and if
there is high blood pressure,which could be the case, then
just treat it as such and thenwait until they're an adult age,
then discuss when it's theright time to be screened and
get diagnosed.
But definitely for our patientswho are 18 and above or
(18:22):
individuals at risk.
So anyone who has familyhistory of ADPKD and there are
18 or above they should starttalking about.
Okay, should I go get screened?
" Talk to my doctor, get thekidney ultrasound and the only
caveat to getting screened earlyis there might be a risk of not
getting a life insurance.
So they need to kind ofconsider that and then either
(18:42):
get a life insurance beforegoing and getting screened.
But the earlier the diagnosis,the earlier we start treatment,
the earlier they're proactiveabout their health, the more
benefit they're gonna have.
But it's definitely there's nokind of one answer for everybody
, because some of our youngerfolks they need to go through
college and they need to passthrough some milestones in life
(19:06):
before they get this bigdiagnosis, so it's very
different for each of them.
Dr. Michael Koren (19:09):
It's a heavy burden psychologically.
Yeah understood.
So you mentioned the vasopressinantagonists and we'll call them
Vaptans to make it easy.
I know there was a number ofthem that are being studied.
Are there others on the marketnow 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 othertypes of Vaptans.
There was one that was about togo into larger clinical trials
but they stopped doing that.
The main kind of benefit ofthese other Vaptans is trying to
see if they don't affect theliver and so there's less need
(19:47):
to do all these monitoring, soless burden on the patients.
But all the Vaptans will havethe same effect of drinking a
lot of fluids because that's howthey work.
So there's potentially otherformulations, maybe longer
acting, maybe there's othertypes of Vap tans.
For example there's a study onsnake venom that can cause, that
(20:08):
, 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.
But they're still very early in.
Dr. Michael Koren (20:17):
And are there any other classes of drugs that
are specifically approved fortreating polycystic kidney
disease?
Dr. Fouad Chebib (20:23):
So other than blood pressure control, which we
favor, the first line is ACEinhibitors or ARB.
Those are kind of the firstclass types of blood pressure
medications.
The only FDA approved treatmentis tolvaptine, and the others
are still in clinical trial.
Dr. Michael Koren (20:39):
So the classes of blood pressure
medicines that you mentionedultimately block a hormone
called angiotensin II and thathas specific effects on the
cysts, or just general good forreducing proteinuria and things
like that.
Dr. Fouad Chebib (20:52):
Yeah, so with PKD we expect very little bit of
proteinuria, so less than onegram, but the main effect is.
So there has been a lot ofhypothesis, a lot of studies,
that blocking the pathway of theangiotensin pathway could slow
the disease progression and thatled to a very large study
within the US called HALT PKD,H-A-L-T, P-K-D and trying to
(21:19):
look at giving two types, so theACE inhibitors and the ARV
together, and also targetingmuch lower blood pressure target
.
So one arm was 110 over 75 orless, actually between 95 to 110
, and then the other was the 120130 and the study was called
negative but the p-value was0.05.
Okay, and what was significantis that in the group that was
(21:42):
treated much aggressively on theblood pressure target of 110
over 75, the kidney volumes orthe cysts grew a little bit less
faster, so 6% versus 5%.
It was significantstatistically and that's where
the recommendation now from PKDgoes for patients who are
younger and at risk of rapidprogression, let's target 110
(22:03):
over 75.
Dr. Michael Koren (22:04):
Got it.
So just for the lay audienceout there.
We got a little technical therewith p-values and things, but
it was a borderline study.
But the gestalt is that there'sprobably some value to go lower
and use the class of drug thatblocks 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 intrials.
It's still a good idea to keepthe blood pressure lower for
these patients, as long as theytolerate it.
Dr. Michael Koren (22:33):
Got it.
You mentioned a little bit ofdietary things.
Any other words of wisdom forpeople in terms of how strict
they need to be with their dietif they have PKD problems?
Dr. Fouad Chebib (22:44):
Yeah, there's a lot of interest from our
patients and from the scientificcommunity on interventions on
diet.
Now it's very interesting forPKD we think it's a metabolic
type of disease, so there'sissues with the mitochondria,
the powerhouse of the cell,where in PKD that's affected,
and so we think that if we dosome interventions on the diet
(23:07):
we can reprogram how the kidneycells 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 onketogenic diet, on giving some
either medical food or othercompounds to kind of reprogram
(23:31):
the mitochondria.
So all these are still inclinical trials.
There's a lot of studies underwhat we call preclinical, so
animal models who have PKD.
They were given theseinterventions, either
restricting calories or doketogenic diet or do some
beta-hydroxybutyrate, which iskind of the ketogenic form that
(23:52):
is given as a supplement.
So all these were positive inanimal models.
There's not a lot of big trialsin humans.
So we came up actually withwhat we call the PKD diet and we
said there's a lot of evidencethat if you're overweight your
disease is gonna progress faster.
So let's bring down that weight.
And the most efficient way, orthe safest way that is now for
(24:16):
other weight loss, is to docaloric restriction.
And even if you cut down by 10to 20% of your calories and keep
your body mass index close tothat 20 to 25 range, then you're
probably gonna gain a lot ofbenefit years.
The other restrictions become.
We don't like to restrictprotein unless the kidney
function is low, so that'ssomething 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 restrictingprotein, 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 isabove 30 milliliter per minute
or for patients they think it's30, or they know about it as 30%
then we could go.
.
.
we don't have to restrict toomuch.
So 0.8 gram per kilogram ofprotein up to 1.3 gram per
kilogram per day If their kidneyfunction is less than 30, then
we start doing some morerestrictions.
If they're on dialysis, it'scompletely opposite.
(25:09):
We want them to be on becausethey get malnourished and they
lose a lot of the energy and theprotein.
We want them to be on heavyprotein.
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 theystart seeing a lot of these
restrictions, is to talk to aPKD dietician or a renal
nephrology dietician and theycan guide them through these
other restrictions.
And as the kidney function goeslow, we restrict potassium,
phosphorus, other things, butsodium.
Water weight is kind of keyearly on in life.
Dr. Michael Koren (25:41):
Right.
So we're both research peopleand we like to look at the
future.
We perceive that part of ourrole as physicians is not only
to do what's known today, but tofigure out what to do for
tomorrow.
So give us a little insightinto what people are thinking
about in terms of what we'regoing to do tomorrow for people
that have PKD.
Dr. Fouad Chebib (26:02):
Yes.
So it's very, very exciting inPKD in 2025, 2026, because all
the scientific advances thathappened over the 10 to 20 years
, mostly over the last five to10 years, has now culminated
into things that we could starttesting in humans, not only kind
(26:24):
of talk about it in the papersand in animal models, right.
So all this kind of work nowit's almost at the same time
coming together.
There's also interest fromindustry or pharmaceutical
company where they did a lot ofthe research and development.
They took all the otheracademic scientific work and
moved it on to potential newtreatments, and so definitely
(26:48):
there's a big unmet need.
There's a big gap in takingcare of our patients because,
yes, we talk about how we keepthem healthy, but we haven't
talked about how to completelyprevent kidney failure.
So completely preventing kidneyfailure, that's my lifetime
goal.
Dream is when patients come tome I'm like, okay, we're gonna
do this, this and this and youdon't have to worry about
(27:10):
dialysis, transplant.
We're not there yet.
I keep promising my patientsand our community.
Five to eight years maybe iskind of my goal, and by that we
talk about gene therapy, aboutcures, and that's gonna happen.
We have a lot of initiatives.
At Mayo Clinic Florida, forexample, we have now an organ
perfusion studies unit that Ico-direct and we're working on
(27:31):
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 whatwe call cold perfusion.
So there's just kind of a pumpthat 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 kidneysto kind of not be as happy and
then it goes into the recipient,the patient who needs that
(28:03):
organ transplant, and usuallythat kidney doesn't work well
right away.
It takes some time, so there'ssome injury or kind of issues
that happen with the tubules ofthese kidneys.
So what we're trying to createis to perfuse the kidneys or
livers and keep themmetabolically and
physiologically active.
So we want to keep thesekidneys that we take out, that
(28:26):
were not good enough to go andget transplanted in a patient,
put them in our perfusion system.
That's warm perfusion with newliquid new fluids and a system
that keeps that kidney makingeven urine for almost three days
and by doing that it becomes aplatform to test gene therapy or
(28:47):
other rejuvenating, anti-agingkind of processes.
Doing the same for the liverfor two weeks for the liver.
Dr. Michael Koren (28:54):
So there's thoughts that we can eventually
fix the gene that's responsiblefor the problem.
Dr. Fouad Chebib (28:59):
Yes, so, as you know, with gene therapy now
it became also extremelyadvanced over the past 10 years.
You know you can go in and justkind of edit one change in the
DNA and there is a lot oftherapies that are now well,
there's FDA approved therapiesfor gene therapy.
The kidney is quite challenging, so one is, the kidney protects
(29:23):
itself.
So it's very hard, verychallenging to get these vectors
, whether it's a virus orsomething non-viral vectors, to
go and deliver these tools tofix the kidney, the cells.
So the first thing is how can weget it to the kidney?
And then how can we get it tothe right place in the kidney,
and then what is within thepackage, what should go into the
(29:45):
kidney?
So these three things if wekind of overcome and I think
technology is helping us how todeliver directly to the kidney,
there's kind of almost like abypass on the kidney.
Uh, you know, while the kidneyis still in the body we can
perfuse it for two hours notaffecting the other organs
interesting and deliver this.
There's a lot of advance on thevectors, on how to deliver and
(30:07):
then understanding the genetics.
Now there's also more advanceson what should go in and get
fixed.
Like what is that tool?
So hopefully, with liningeverything together, that's kind
of my dream is to start doingthese procedures where patients
come in early, even at youngerage, at 12, 15, will go in, fix
(30:28):
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 eightyears 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,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 dowith growth factors.
Just briefly mention that orany others that look
particularly promising in sortof the short to intermediate
term.
Dr. Fouad Chebib (30:59):
Yes, absolutely.
So before we reach the stars westill have some relatively low
hanging fruits.
So in any disease we wanna slowit down if we cannot completely
prevent it.
So we don't want the perfect tobe the enemy of very good.
So the very good that's now inthe next three to five years
it's going into clinical trialsand there's a lot of science and
(31:20):
great science actually behindit.
So there's multiple things thatare now ongoing.
So you know, think about thesekidney cysts.
So in addition to that,vasopressin or the thirst is
stimulating the fluid secretion.
Also, these cells are kind ofproliferating or they're kind of
doubling up with time.
So then you can create thisstructure right.
(31:43):
It's almost like a benign, mass, benign tumor.
It's growing, it's fillingfluids but also it's growing in
size.
So if we can find somethingthat's tolerated, that's almost
like stops the proliferation orthe growth of these kidney, it
would be perfect, right?
So with studies actually done atMayo Clinic, Florida with Dr.
(32:05):
Eduardo Chini, he found out hewas working, he's actually a
scientist, a physician, and ascientist works on anti-aging
processes and he found throughthe anti-aging process that
there's a growth factor that ifyou target it you stop PKD from
growing.
So if you create, for example,an antibody that prevents the
(32:29):
cleavage or the, so let's kindof step back.
So you have kind of a growthfactor, you have a receptor.
That receptor, if it getsstimulated, the kidney is being
stimulated, so it's InsulinGrowth Factor Receptor.
Now for that to be stimulatedit kind of comes as like a key
and like a two pieces, and ifthose two pieces are still
(32:52):
together then you cannotstimulate the growth factor.
So naturally there's somethingthat comes and breaks them apart
and then it stimulates thegrowth 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 kindof opening up and then there's
no more growth factor free to bestimulated, 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 totreating PKD may be coming to a
clinical trial center near youin 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 wehave a lot of options.
Again, some patients don'ttolerate Tolvaptine.
They cannot be on Tolvaptinebecause they have work.
They cannot be in bathroombreaks every so often, so that
gives them a lot of options andthere's a lot of studies behind
this and we hope that it's safe.
(33:56):
We think it's safe.
Dr. Michael Koren (33:58):
Any other approaches other than the growth
factor approach that peopleshould know about?
Dr. Fouad Chebib (34:02):
Yeah.
So there's other kind ofapproaches as well.
So there's what we callanti-microRNA.
So with PKD, again one copy isnot working, one copy of the
gene, so that DNA is defected.
So the protein that's supposedto be made out of that copy is
(34:23):
what we call less functional.
So there is less of thispolycystin, one protein or
polycystin two.
So these are the proteins thatif you have less of, then the
kidney starts making the kidneycyst.
So there's an approach whereyou know just also stepping back
.
So DNA goes to messenger RNA,then goes to protein.
So typically in a natural waythe cells are making these
(34:49):
messenger RNA and then they'redegrading them or they go away.
You make more and so forth.
There's a process where itcomes and particularly for the
PKD1 and polycystin1, it stopsthat messenger RNA from being
degraded.
So you keep kind of themachinery and the factory.
You overwork almost your otherparents.
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 moreof that protein Interesting.
That's the concept.
It went through the first phaseof phase 1B Interesting and
it's going into phase 3.
So that's one option.
And then there's another set oftreatments.
That's also very exciting, butit will only right now, for the
(35:42):
first part, it's gonna be onlyfor 10% of patients with
specific area where they havethe PKD1 mutation.
So PKD1 is one of the largestgenes in our body and it's a big
protein.
But if some of these mutationsor these changes in the DNA, the
protein, what happens is itgets misfolded and stuck in the
(36:04):
endoplasmic reticulum.
So almost like you make it inthe 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 unfoldit and then sent and patched it
up just to go there.
So there's, those are going tocome into trials also.
(36:26):
End of this year.
It's gonna be an oral medicationand it's only a small portion
of patients.
So again, a lot of excitement.
Not all these options are forall the patients.
So what's exciting to me inclinic is when I see our
patients, I give them the optionof the standard of care first.
This is what we need to do.
(36:46):
If you're eligible for tolvap,then let's try it.
If you don't feel this is theright thing, we definitely need
to go to clinical trial, andthat's how we advance, not only
for our patients but, also fortheir kids.
And that's the unique thingabout PKD they're always
motivated because not only forthem they want to fix this for
(37:07):
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 largestclinics in the country and it's
very exciting.
So we have a kind of processwhere our patients come in.
We have myself, our co-director, Dr.
Mao, and then two of our nursepractitioners and we follow
quite a large number.
Dr. Michael Koren (37:28):
Wow, Very nice.
Well, this has been afascinating discussion.
Thank you so much for sharingall your knowledge.
It's been amazing.
I've learned a tremendousamount and it looks like we're
on the precipice of a lot ofreally exciting things in this
space and I'm looking forward tobeing part of these advances
hopefully in the very, very nearfuture, but a lot of different
(37:53):
ways that we may be able toimpact 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 forshedding 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 stayat home.
There's a lot of things you cando 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 agreat researcher, and how to get
in touch with us in terms ofresearch opportunities
Absolutely researcher and how toget in touch with us in terms
of research opportunities,absolutely so.
Thank you again for being partof MedEvidence.
Thank you for having me.
Announcement (38:27):
Thanks for joining the MedEvidence podcast.
To learn more, head over toMedEvidence.
com or subscribe to our podcaston your favorite podcast
platform.
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