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Atherosclerosis
Cardiac events are the #1 morbidity/mortaility in
chronic kidney disease.
Why?
§
Uremia and dialysis are pro-inflammatory states.
They promote atherosclerosis.
§
Calcium-phosphate overload worsens coronary artery
disease (this is why it is an A)
So
what do you do?
Modify risk factors
§
Smoking cessation
§
Lipid control
especially with statins (HMGCOA reductase
inhibitors).
§
Statins decrease heart problems in people
without chronic kidney disease.
§
So
you would think it would make sense that people with
chronic kidney disease would have the same benefit, but
it has not shown to be true.
§
So
at least Dr. Kaplan prefers to be safe and normally puts
his patients on them to ensure lipid control and maybe
get the additional benefits of lowering risk of heart
problems.
§
Calcium/phosphorous control
§
Blood pressure control
§
Glycemic control
§
Role
of anti-oxidants???
§
It
would be logical that vitamins would help since uremia
and dialysis are pro-inflammatory and the inflammatory
damage would be lessened if we gave anti-oxidants.
§
However, there have been no studies to show that
vitamin have any benefits.
§
They
do not decrease death or problems associated with
chronic kidney disease.
§
But
another antioxidant acetylcystine has been shown to
help dialysis patients with respect to heart
disease, but is smells and tastes like rotten eggs
due to the sulfur in it and patients do not like
taking it.
So
what happens with the calcium-phosphate homeostasis
in chronic kidney disease?
§
It
becomes unbalanced.
§
You
get decreased clearance of phosphate by the kidney,
and that elevates serum phosphate levels and
stimulates parathyroid hormone (PTH) secretion.
This will cause hypercalcemia
§
The
kidney also synthesizes less 1,25-vit D which
decreases serum calcium, increases serum
phosphate and will cause PTH secretion to
increase.
§
This
gives you secondary parathyroidism, which
increases calcium levels and gives some interesting
immunomodulatory effects we do not need to know about
right now.
So
why do we care?
People with elevated phosphorous and elevated
calcium-phosphorous products (calcium concentration
times phosphorous concentration) have increased
mortality and morbidity, probably due to
increased arteriolar calcification. The calcium and
phosphorous will form calcium phosphate and will
precipitate in arterioles, especially the
coronary arteries. This will cause heart disease.
So
how do you deal with the disorder?
§
Low
phosphorous diet
§
Phosphorous binders
§
Calcium,
like tums, but this will also increase calcium
and the calcium phosphorous product.
§
So
you can take “non-calcium” phosphorous binders.
Aluminum is a great calcium binder and was used
but it can cause toxicity. Renagel is a
good one that is used right now. Also, lanthanum
is a new heavy metal that is starting to be used.
§
You
also need to work on the secondary
hyperparathyroidism, and that can be treated with 1,25
Vit D and its analogues.
§
Analogues are preferred
since they will raise the calcium phosphorous product
less than 1,25 Vit D.
§
Also
there are calcium sensing receptor modulators (calcimimetics).
They act like calcium to stimulate the calcium sensor
which decreases parathyroid hormone secretion
while not raising calcium levels.
How
low do we want the levels?
§
Phosphorous below 5.5
and the lower the better.
§
Calcium of less than 9.5
§
A
PTH level 2-3 times normal.
§
Why
so high?
§
There is a truncated PTH protein that actually works
against PTH.
§
It
is in essence an anti-PTH.
§
But
our assays do not differentiate between the two.
§
So
people with chronic kidney disease have equal levels of
PTH and anti-PTH.
§
So
if you can lower the PTH to 2-3 times normal, most of
the “PTH” being read on your assay will be the truncated
PTH, which is beneficial to patients with chronic kidney
disease.
Now
we move onto blood pressure
§
Many
studies have shown that BP control slows the
progression of chronic kidney disease and also
reduces cardiovascular risks.
§
The
target BP is officially 125/75 for people with
kidney damage, but it keeps lowering.
§
There has not been any evidence of a floor effect
(the benefit of lowering blood pressure stopping when a
certain BP is reached), so the lower the better.
ACE-I/ARBs
§
These drugs have been shown to reduce the progression
of chronic kidney disease independent of blood pressure
effects, except for polycystic kidney disease.
§
These drugs have a primary anti-proteinuric effect,
since they decrease glomerular filtration pressure
by dilating the efferent arterioles (leading away from
the glomerulus) and prevent dilation of the afferent
arterioles (the ones leading to the glomerulus).
§
Studies have also been showing at least an additive
effect when you combine ACEs and ARBs.
§
So
when can’t you give them?
§
When
people have angioedema (an allergic reaction)
§
Hyperkalemia
since these drugs raise potassium
§
If
someone has a Glomerular Filtration Rate that is too
low, you cannot give it to a patient because a
primary effect of the drug is to lower Glomerular
Filtration Rate.
§
Dr.
Kaplan uses a general rule of not giving it to
someone with a Glomerular Filtration Rate lower than 15,
since it will send them into a need for dialysis.
§
Also, you can’t give it to someone who has a functional
Glomerular Filtration Rate because of angiotensin II.
This could be the case if Angiotensin II is causing
vasocontriction of the blood vessels in the kidney and
maintaining pressure in the glomerulus when there is
decreased volume of blood or blood flow to the kidney,
like renal arterial stenosis. Giving the drug will
lower angiotensin II levels and cause the patients
Glomerular Filtration Rate to plummet.
§
Now
he showed a graph of kidney function, which cannot be
included because his slides are not on WebCT. But
the graph shows that the Glomerular Filtration Rate of a
patient not on ACE-I or ARBs drops at about 15-20 per
year. If someone is put on an ACE-I or ARB,
there is an immediate drop in Glomerular Filtration
Rate, but then it levels off, due to blood
pressure control and the primary beneficial effects. So
ACE-I and ARBs delay the need for dialysis.
Hemoglobin A1C
§
Glycemic control reduces rate of progression of chronic
kidney disease,
not just in diabetic nephropathy, but in all chronic
kidney disease since glycemic control decreases all
of the end-stage problems in diabetes.
§
Glycemic control also reduces the risk of coronary
artery disease,
which is very important because it is one of the main
reasons patients with chronic kidney disease die.
Anemia
§
First you must rule out other causes of anemia,
such as GI cancer or iron deficiency,
which is common.
§
Since it is the kidneys that make erythropoetin, chronic
kidney disease will cause a problem in its production.
These patients have a relative erythropoetin
deficiency. The level may not seem low, but considering
the patient has anemia, it is abnormal. Erythropoetin
levels are rarely checked anymore and normally you just
go right to treating with erythropoetin analogues, such
as epoetin. However, you need to make sure the patient
has iron and give iron supplements if needed for the
epoetin to work, otherwise the anemia will persist.
§
There is also epoetin resistance, but Dr. Kaplan did not
talk about that much.
§
So
to treat anemia we look at Fe, ferritin, and TIBC
(Total iron binding capacity).
§
If
the patient has a normal ferritin but iron
saturation is low, they have a functional iron
deficiency and that must be treated with oral or
IV iron unless the ferritin is above 600.
§
This
number may vary depending upon hospital or doctor, but
Dr. Kaplan uses 600 as his cutoff to not treat with
iron.
§
We
treat anemia aggressively because patients with
chronic kidney disease and anemia do worse than chronic
kidney disease patients without anemia.
§
They
get left ventricular hypertrophy due to needing
to pump more blood to get the same amount of oxygen to
the body.
§
People feel better and have better performance status
when they are not anemic.
§
Also
there are immune aspects to anemia, where people have
weakened immune systems with anemia.
Acidosis
§
You
can get a type I or type IV (which causes
hypocalemia) renal tubular acidosis due to
loss of nephrons and inability to excrete daily load of
acid.
§
The
acidosis buffered by bone, so it causes bone diseases.
§
You
treat the acidosis with bicarbonate or citrate,
but this causes a problems since you treat with sodium
bicarbonate or potassium citrate, which will cause
sodium or potassium overload.
Now
we go onto treatment for end stage renal
disease.
§
Renal replacement is the main method
§
It
consists of hemodialysis, peritoneal dialysis, and
transplant. Another “treatment” option is death
if the patient is not really well enough to treat
effectively or if treatment is not feasible.
§
The
criteria for treatment are…
§
Uremia-You
do not want to wait for when people get a “uremic frost”
in their urine to start treatment. Look for poor
appetite, nausia, vomitting, falling albumin, weight, or
feeling rotten as early signs of uremia. Feeling
rotten or ill is often overlooked since people get used
to the slow progression to feeling bad, but is
important.
§
Intractable volume overload-it
is hard to get this since doctors can give plenty
of diuretics to prevent this.
§
Rarely given for acidosis or hyerkalemia
So
what is dialysis?
§
Well
if you take a bag, filled with fluid and put it in
another liquid and stuff will diffuse into and out of
the bag.
§
So
hemodialysis is when you take blood from a patient at a
very high rate, and run it through a high-area dialysis
membrane, with dialysis fluid running in the opposite
direction. The bad stuff in the blood will flow out of
the blood into the dialysis fluid and the good stuff
from the dialysis fluid will go into the blood.
§
The
blood is then returned to the patient.
§
What
are the problems with dialysis?
§
It
gives you an oxidative surge due to exposure to
the dialysis bag.
§
It
only gives you a very low Glomerular Filtration Rate,
only about 10 or 15. It does not clear calium and
phosphorous well and can’t get rid of uremia. Short
daily dialysis and nocturnal dialysis do a much better
job, and they will probably start in about 3-4 years.
So
how much is enough?
§
US
standard is 3-4 times a week, 3-4 hours per treatment,
which gives you a urea clearance of >65% per treatment.
§
But
in
France,
the mortality rates are lower partially
because they do longer and more frequent dialyses.
§
So
currently we are looking into either shorter daily
dialysis or nocturnal hemodialysis, where the
treatments are done at night, during rest.
§
The
more frequent dialysis treatments are beneficial
because they reduce the volume variation, since
you are more constantly reducing the fluid volume
of the patient rather than just 3-4 times a week. This
helps reduce the stretch on the heart.
§
Also
it decreases time-average urea, the amount of
urea in your body averaged over time, which may help
the overall uremia.
§
Longer treatments are more beneficial because it
helps increase the clearance of phosphates and “middle
molecules”, which is time dependent. Doctors are
not sure what these middle molecules are,, but they
exist and it helps to get rid of them.
§
It
is also more easily tolerated since there are no
rapid shifts in concentration.
Never forget about diet in patients with end stage renal
disease.
§
These patients should get a low potassium, low
sodium, and low phosphorous diet with fluid restriction,
which seems pretty boring.
§
The
one thing you should not restrict is protein,
even though you would think it would be beneficial with
these patients have proteinuria and since protein can
cause uremia.
§
But
lack of protein will cause malnutrition,
which as we mentioned before it very bad for these
patients.
So
what about peritoneal dialysis?
§
A
catheter is put into the peritoneal cavity, and fluid is
put into the peritoneal cavity.
§
The
patient is given as much fluid as they can tolerate,
normally around 2-2.5L.
§
The
peritoneal membrane is used as the dialysis bag
with the blood being inside the membrane.
§
The
fluid is changed periodically through the day or
night and patients are dialyzed 24 hours a day,
which makes it a nice smooth treatment.
§
But
it is not as powerful as hemodialysis.
§
The
main complication is peritonitis.
§
We
do not do much peritoneal dialysis because we prefer to
have patients do hemodialysis unless they can’t take it.
§
In
Canada,
they do peritoneal dialysis unless a patient cannot take
it. There is no real reason to prefer one of the other.
Transplant
§
Patients receiving transplants live longer and are less
expensive.
§
Patients on dialysis cost about 60-100K per year while
patients after transplant only have 10-20K worth of
immunosuppresive drugs to take per year.
§
The
problems with transplant are not enough organs,
patients have acute and chronic rejections, which
the medicines are given for, and then the
complications from these medicines.
So
what are the types of transplant?
§
Cadaveric transplantation-a
person with brain death (the heart is still beating) can
donate their kidney after being declared dead since the
kidney is still being perfused and is not damaged. But
this type of death is rather rare.
§
Now
people are starting to look at cardiac death donors,
but the problem is that the kidney starts getting
damaged early since when the heart stops beating, the
kidney stops getting blood. But although these organs
are “less good” than the ones from brain death donors,
they are better than dialysis, so there is a push to do
more of these transplants.
§
Living or unrelated donors-These
are the best kidneys, since you can take it out and put
it on another person quickly without having much or any
damage.
§
Combined organ transplant-works
great in someone with diabetic complications because you
can give someone a new kidney and pancreas or pancreatic
tissue to help control the diabetes.
§
One
idea could be to use non-human organs, or
xenotransplantation. But the problem is that there are
animal viruses that could infect the human and normally
animal viruses that infect humans are far worse than
normal human viruses.
§
Transplants are normally matched by HLA types. A 6 out
of 6 match is perfect and preferred, but a 5 out of 6
match is just as good as a 0 out of 6 match.
But
what are the complications of the immunosuppressive
drugs?
§
Increased infections
§
Increased malignancies
§
Lots
of drug interactions
(which is a problem in patients on a lot of long term
drugs, like patients with chronic kidney disease)
§
One
goal of transplantation is getting tolerance to these
drugs. In Pittsburgh, they have looked at lower dosages
of drugs to help enable tolerance to the
immunosuppressive drugs.
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