So it's a pleasure to have the

opportunity to talk to you

about polycystic kidney disease.

And until then.

Oh, yeah.

Until the nineteen nineties,

the polycystic kidney disease

or polycystic autosomal dominant

polycystic kidney and liver disease

was considered to be a single

inherited disease.

But since that time, we have

found that is a very

heterogeneous genetic disease

with two main genes, 81

and 82, but now

an increasing number of other genes

that can also cause polycystic

kidney and or liver disease.

Now,

the prognosis

is much

better in patients that have the

disease associated with the two

mutations than patients

that have the disease associated

with one mutations.

And the patients that have PICADILLO

mutations can be divided into two

groups, those who have

completely inactivating mutations

or truncated mutations

that have the worst prognosis with

the enter stage in their 50s

and those that have MS.

says mutation that still produce

some protein that is not normal,

that have their enter stage in

their 60s as opposed

to the pykrete imitation they have

at this stage in their 70s or

never.

Now, the difference between 81

and 82 is the number

of cysts, with 81 patients

having many more seats than

typically two patients.

And this is develop a very

early, very early in

life.

Now, the patient to

have her polycystic

kidney disease very frequently,

almost always happens overseas as

well, but they also these

patients that have polycystic liver

disease without cysts in the

kidneys or very few in the kidneys.

And this is autosomal dominant

polycystic liver disease.

And the two main genes causing

some abdominal polycystic liver

disease are Perkasie, S.H.

and 63.

Now, the difference between these

two most of the time is very clear,

however, it's not always

the case and you can't have patients

that have very severe polycystic

liver disease and only a few cysts

like these two cases.

And one of them has a mutation in

the piggery, one gene and the other

one has a mutation, the CSA

gene.

So without genetics would be very

difficult to differentiate these two

patients. Of course, the family

history helps a lot in these cases.

Now, do any other cases,

maybe all the genes can be

associated with polycystic with

cells in the kidneys or the liver.

And one of them is the case.

They one gene, which one is

inherited is homozygous.

Manitas have two mutations, causes

autosomal recessive, polycystic

kidney disease and the heterozygous

carriers of the disease.

About 15 percent of them

can capsaicin in the kidneys or

deliver some

other genes that are associated with

a mild form of polycystic kidney

disease and polycystic

liver disease that can range from

mild to quite severe.

And one of them is collagen and

another one is called Algate.

Another one is called alginate.

All these patients have mild

polycystic kidney disease and very

rarely advanced to enter stage

kidney disease or almost never.

But the polycystic liver disease can

be severe.

Another that has been associated

with the difficulty is the energy

live, and this is quite a different

phenotype because the kidneys

are not in large but

contain cysts

and there is a discordance

between the size

of the kidneys or the volume of the

kidneys and the severity of the

disease. And these patients do

developmental stage kidney disease,

but they developmental stage kidney

disease, usually after 60 years

of age.

So the late, late onset

to enter stage.

But again, there is a discordance

between the size of the kidneys,

the appearance of the kidneys and

the decline in kidney function.

So all of the genes and code

proteins that are important are

required for the proper maturation,

folding and folding and traffic

of the resistance

and other membrane and secreted

proteins.

So these have kind of this common

pathogenesis and it's mediated

by defects in the public systems.

Now, the patients that have

mutations in DNA should be labeled

in some way.

They are quite similar to the

patients that have autism, somewhat

dominant interstitial kidney

disease, which is associated

with mutations in neuromodulation

and mokoan.

The difference between the energy

level and these ones is that in this

in this patient, Gaute is very,

very prominent, whereas

patients that have the energy

believe in God is not as prominent.

And also this patient rich

inter-state kidney disease at an

earlier age.

But also some of these patients are

frequently confused with patients

that have or somewhat dominant

polycystic kidney disease.

So with all this background,

what are the indications for genetic

testing? Well, one has to think

about genetic testing.

When you have a patient, when there

is a discordance between the way the

kidneys look and what the function

is, or a typical presentation,

like a patient with polycystic

kidney disease that have

been eaten by Adelphia's uterus

or have had magnesium, then

you have to think about the

possibility of an H.F.

one bit and if one bit

a mutation or discordant

phenotype within the family, which

usually point to the presence

of two different mutated

genes in the family or the presence

of more racism, or in

patients that have no family history

that the first cases.

So in this case is this genetic

testing is helpful to establish

their noses. And then there are

situations where you want to

consider genetic testing,

which is in the evaluation of kidney

donors when the imaging is not clear

or in preimplantation genetic

diagnosis, and then also for

establishing a prognosis for

individual patients.

Now, the policies in one end,

policies tend to work as complex

and they are located in the primary

cilia, but also in other

locations like the plasma membrane

and the palm reticulum and other

similar locations.

And these proteins together

control the homeostasis

of intracellular calcium and

intracellular calcium, regulates

the formation and destruction

of cyclic can be so

impatient with polycystic kidney

disease, there is an accumulation of

cyclic MP and activation

of protein KENENISA, which

result in activation of chloride

secretion and fluid secretion

and activation of many proliferative

pathways and

formation of growth factors and

cytokines that result in

the production of polycystic kidney

disease.

Now all of these mechanisms have

been targeted to experimental

therapies, but only to

have been so far

clinically important, which is

two pathways

that are important regulating the

cyclic production

in the cells that originate

the system, polycystic kidney

disease, which is the DNA from the

collecting dust and these individual

pressing Bittu receptor and

the somatostatin receptor.

So the drugs that inhibit the

formation of cyclic MP by block

individual person B to receptor

or by a debate in the somatostatin

receptors had been used

in clinical trials and

some in clinical practice.

Now one of the important first

findings was observe with a

three month trial that then we

thought pattern of polycystic kidney

disease is that acutely

it produces a reduction in EGFR.

And the reason for that is very

clear, which is very surprising

physiologically by reducing

the amount of sodium and the macro

then inhibits the Tupelo

glomerular feedback and induces

a by the dilatation and increases

the EGFR to a drug

that blocks the video pressingly to

reception receptor,

reverses that and result in an

acute reduction in EGFR.

This was an important information

in designing the clinical trials

of two of them because it said

that you have to compare on

treatment one treatment or of

treatment of treatment in order to

determine the fate of GFR,

but is also very important to

understand why when you start the

patient on that, then there is

actually a reduction in EGFR.

Now, there have been two main

clinical trials of tobacco for

polycystic kidney disease and

possibly for in patients that have

relatively preserved kidney function

and with EGFR of 60 and

represent patients that have a GFR

between 25 and 65

and then an open label extension

and some stock analysis.

Now, the temporary four showed a

reduction in the rate of increase in

total kidney volume by 49

percent,

temporary for underpressure

reduction in the rate of decline of

GFR. That was more clearly

shown in patients who were already

losing kidney function in

preparation.

It showed a reduction in kidney

pain and into

the open label studies.

And a long term studies have shown

that the effect of tobacco is on.

The decline of EGFR

is persistent over time,

sustained and cumulative over

time.

And based on the result of piece,

one can extrapolate that one,

start the treatment with

a patient with EGFR of 60

can prolong the life of the kidney

by approximately six to seven years.

If you start later, the benefit

is smaller.

Now, there is a problem with all,

but then one of them, of course,

is a poor area, which usually

is not the main issue because the

patients get used to that.

But the five percent of the patients

have elevations in liver enzymes,

which is concerning, and in the

temporary forward level that will

monitor only every four months.

There were two patients that had

severe liver dysfunction

meeting the highest law criteria.

Both of them fortunately recovered.

But once we get to that point,

there is a risk of hepatic failure.

And when in

the study, however, although there

were five percent of elevations of

liver enzymes, there were no severe

cases of hepatocellular injury

because these patients were

monitored during monthly

during the first 18 months of

treatment during which is

most of these allegations of liver

enzyme occur.

Now, in terms of a somatostatin

analogs, there have been three

large clinical trials focusing

on the kidney effect, Aladin, one

Dipak and two

patients with Secada,

two, three or four.

And what these studies have shown

is that there is a significant

reduction in the rate of kidney

growth.

However, no effect on the

rate of the EGFR decline

was observed, although

in one study there was a trend

to reduce TFR decline after

the first year, and in the

earlier study, there was a reduced

proportion of the patients

that had a doubling of student

creatinine or interstate's

kidney disease.

So to summarize, the current status

of the somatostatin analogs for

polycystic kidney disease is

an agreement.

There is a reduction in the rate of

growth, but there is no clear

effect on GFR decline, at

least not demonstrated until now.

There are a number of other clinical

trials are ongoing, which I won't

have time to go in detail.

But there is a multi

kinase inhibitor block,

a drug that blocks the formation

of Lucasville Sellami that

accumulates in the kidney, amazed

that they can grow the

seeds grow faster.

Bardock Salon, which activates

the transcription factor that

regulates the network of antioxidant

and anti inflammatory

genes.

And let's see Vatan, which is like

to back then but has been predicted

that may not have the liver

toxicity that Alberton has.

And then there is a phase one study,

which is kind of a noble study

because it's completely new

approach to persistent kidney

disease. Eugene Dimir,

Oregon. Nucleotide repressors,

policies and policies tend to also

increase the expiration of policies

and policies to.

So all of these studies are in

progress and whether they will be

successful or not remains to be

seen based on

what has been done to that.

That has been approved

in many counties.

For the European polycystic kidney

disease has been approved

only with four patients that have

rapidly progressive disease, which

presents the problem of how you

define rapidly progressive disease.

Genetic testing, as indicated

before, is a gift, is

in populations, is helpful,

but at an individual level

is not very helpful.

These are patients from all

of these patients, Category one

mutations, and some of them have

very mild disease and some older

patients of similar age

have very severe disease.

So genetic testing is predictive

in populations, but in individual

cases is not always perfect.

So because at the present time,

the the only biomarkers

that have been approved by

regulatory agencies are prognostic

biomarkers and estimated

GFR and total kidney volume

adjusted for age.

However, NGF

GFR is helpful in patients that

have the disease when they

start declining Bando in the

first decades of life and

the GFR can be perfectly normal.

And this is the severe

because during all this time the

kidneys continue to grow

continuously.

And the CRISPR studies have shown

that the growth of the kidney

disease exponential is variable

among patients, is relatively

constant, is unique to each patient.

And in the CRISPR study, we

saw that the increase in total

kidney volume occurs continuously

and precedes the decline in

GFR and not

only precedes the decline in GFR,

predicts the decline in GFR

with a relatively

good sensitivity and specificity.

So this has been confirmed

by a larger study, the bigger

the consortium

and based on the results of this

study, the Food and Drug

Administration and the European

Medicines Agency approve

total in the volume patient

age and GFR prognostic

biomarkers.

Now we have the e-mail image

classification, which is a practical

tool for the utilization

of of these

biomarkers.

And this image classification

starts by identifying about

five percent of the patients with

polycystic kidney disease that

have atypical presentations

with unilateral sematic or segmental

involvement like in

these cases, or ischemic

disease due to old

age or vascular disease,

where the kidney volume cannot

be used as a biomarker.

So the kidney volume is used as a

biomarker in the typical cases of

a kidney.

And these are classified in

five different classes, depending

on the estimated rate of growth

of the kidneys and the estimated

rate of growth of the kidneys can be

obtained from a single determination

of kidney volume

at a particular age,

assuming a theoretical initial

height adjusted kidney volume of 150

miles per meter toward

a patient with a

rate of increase in the volume of

less than one point five percent

patient with Karzai, average

annual rate of the volume

increase of over six percent.

So these patients that are classi,

these are considered

rapidly progressive disease

patients with they they never reach

kidney failure patients with the

kind of agrees on.

So this classification

is predictive of

the future decline of GFR with

a reasonable

estimate, the predictive value,

and also predict the risk

of progression to enter stage

kidney failure and the age

of inter-state kidney failure.

So to measure the total volume,

however, one can use the gold

standard three or

astrology, but both of them

are quite consuming,

so they are not very practical.

To make these more practical

is we have an app

that is available and by just

Googling ADP classification

where you can enter the orthogonal

dimensions of the Kinney's

obtained from either ultrasound,

MRI or C.T.

scan, and this calculates

the kindie volume and image

classification.

Now, fortunately now,

with artificial intelligence and

machine learning has been possible

to develop

software that automatically

measures that can the volume

within a couple of minutes

and we may

have this implemented clinically.

So when we order an MRI

automatically we get the kindie

volume and this is being implemented

in other centers as well.

And finally, there

is also a way to

get the discounting

out automatically.

And this is adds

to the predictive value

of Puttock in the volume.

And this is at the present time, is

still somewhat in development,

but that's something that probably

will be available in a

few years.

Now, in addition to determine

whether the patient has rapidly

progressive disease or not,

then it's important to have

other considerations to determine

whether the patient should be

treated, the trovatore, or should be

counseled to be treated with

Slapton.

And there is not enough time to

go over that. But there is this

article about what should be

that was published a couple of years

ago, which I think is very helpful

in trying to guide

you about whether to

start the patient entrepreneur or

not. One of the most important

things is not to forget about the

optimization of the basic

ADP ATP management,

which is also very important

because although it does not have a

huge effect on the long term

outcome of polycystic any disease,

it has a small effect.

And if you put everything together,

it has a very significant effect.

So one of them is what is the right

target for patients with

CKD one or two in

polycystic kidney disease and

patients? The whole

idea is that the

patient that had rigorous control

with the same blood pressure,

110 over 75 or

less, had a lower rate of

increase in the volume and

the lower rate in the EGFR

after the first four months,

although there was no difference

overall.

However, in the patients that had

the most severe disease would be

much closer than the money they

had, the more increased

benefit from

the regular blood pressure control,

including a reduction in the decline

of GFR overall.

Another study from HOULD has

shown that there is an association

between the sodium intake

and reflected by the

union demonstration and

the rate of increase in total, the

volume and doubling of the same

creatine or interstitial kidney

disease in the study and

in patients study.

B They have more advanced CKD,

CKD, Stage three.

They would have significant effect

in the rate of decline of GFR.

So sodium intake

is very important and the sodium

intake that is recommended is the

two to 2.5

grams of sodium.

Also Holtby, Kerry has shown

that patients that are obese have

a faster rate of decline of kidney

function, that patients that have an

optimal BMI.

And another factor is hydration

with hydration and much sodium

intake. It's important to realize

that maybe the streams are bad

at that, but that the moderate

sodium restriction is beneficial

and a moderate hydration

to maintain a normal ideal

24 hours, less than 280

is beneficial.

And then finally, like all patients,

we could maybe control

and control acid base.

Just a few words about polycystic

liver disease and polycystic liver

disease as opposed to the polycystic

kidney disease. The genetic impact

is not important.

So patients with it, too, can have

severe polycystic liver disease, the

same that patients with one

truncates mutation.

The progression of the disease is

faster in women, premenopausal

women, and it affects

a subset of women.

Some women, you don't see that, but

a subset of women premenopausal

time have very, very

fast increasing in liver

volume, which can be accelerated by

pregnancies.

But after menopause, many of

the volumes go down.

Which is important because when you

decide about whether how to treat

the patient, a female patient with

severe polycystic liver disease

is in the household.

You want to be sure that the rivers

are still growing before deciding

what to do in males is different?

Because we were all the males

have severe polycystic liver

disease, much less frequently

than women.

Believers continue to grow

regardless of the age

for patients that have very severe

polycystic liver disease.

Depending on how the levers look,

they can be candidates for

four forms of therapy,

research on fenestration or

if there is no segment of the liver

preserved liver transplantation

performace.

Therapy is the type of

therapy we use now.

We used to use alcohol in

the past, but we learned from

the group in Toronto that Homochitto

therapy works better and is better

tolerated so that what we are doing

and you can have very good results

with this treatment with especially

in cases that are completely

surrounded by chemo like in

this case, and

also in not only in the liver,

but also the kidney, as

shown in this case here

for patients that have massive

polycystic liver disease and that

there is no surgical intervention

possible, they can be treated

with somatostatin analogs.

This is a study by Murray Hogan

from Mayo, which in

the first year was double blind and

then was open label.

And the patients treated with

octreotide had a reduction in about

six percent in the liver volume,

whereas patients who were not

treated will try continue to have

it all in the open label

phase. The patients that were

switched from octreotide,

from placebo to octreotide,

they had the initial decline

the same then in

the first in the in the

first year.

And the patients that

had the second year of octreotide

have a little bit more decline, but

not a lot.

But however, some patients had

very significant reductions after

40 years, up to

32 percent.

So that's an effective

medication for severe

polycystic liver disease and

something that we were in these

cases when we don't have anything

else to offer that a larger

study recently published

on the group in the Netherlands

showing similar results and

confirming the efficacy

of somatostatin analogs.

And then just finally for a few

minutes, something about the

aneurysm, which is frequently

a question about what to do with

this patient, were to do a

symptomatic screening or not,

that a study that we did

with a patient that would screen

for unknown reasons. I may.

Seventy 75 of them had

any reason that the prevalence of

nine point three percent risk

factors had a family history of

several MCCAMBRIDGE hypertension

and smoking.

Most of them are very small and

most of them are in the anterior

circulation that have a better

prognosis now

in the general population and

five year risk of a rupture of

an annual rate, which is less than

seven millimeters in diameter,

is really very small.

And the question is whether a

patient with polycystic kidney

disease is also a small risk or

a much higher risk

in.

We have followed these 75

patients, a total of 668

patients in years.

We have no ruptures.

About 10 percent of them had

preventive treatment with the

Clippinger calling and

and there were five patients to

develop new aneurysms.

Now, these are dimples of the

stability of the eye, no, for

long follow up.

And bad weather

to screen everybody with polycystic

kidney disease for aneurysms are

not object to the selected screening

is a very controversial subject.

There is a study from France where

they found a very high

risk of rupture, much higher than

we found

in here in Mayo

or in the study for University of

Colorado or study from

China.

So we use this data.

Then it may make sense to do the

screening, but with the rates

of rupture that we have seen,

it doesn't make much sense that

all the

randomized clinical trials are in

the randomized clinical trials.

The incidence of rupture

of aneurysms is

very low.

So based on that, we do not

do a

screening of everybody.

We do selective screening in

patients that have a family history

of subarachnoid hemorrhage, personal

history of several haemorrhage

before major elective surgeries,

high risk occupations, or patients

who are very anxious and need to be

reassured.

And in the patient that we found

aneurysms, even

if the aneurysms

are small and have a low risk of

rupture, which we checked at

six months and 12

months and every three years

annually for three years and every

three years after that.

And of course, it's very important

to blood pressure control and

not not to smoke and

prompt investigation of symptom

sentinel headaches.

And I think that sums it

up. Thank you for your attention.