ERYTHROPOIETIC
STIMULATING AGENTS, HOW CAN THEY BEST HELP PATIENTS WITH CHRONIC KIDNEY DISEASE
Erythropoietic stimulating agents, how can they best help
patients with chronic kidney disease. You are listening to ReachMD, The
Channel For Medical Professionals. Welcome to Focus on Pharmacy. I am your
host, Dr. Charles Turck, PharmD. Our guest is Dr. Sarah Tomasello, PharmD,
Clinical Associate Professor at the Ernest Mario School of Pharmacy at Rutgers,
The State University of New Jersey and a clinical specialist in nephrology at
Robert Wood Johnson University Hospital in New Brunswick, New Jersey.
DR. CHARLES TURCK:
Dr. Tomasello welcome to the program.
DR. SARAH TOMASELLO:
Thank you, thank you very much for having me, I am excited
about this.
DR. CHARLES TURCK:
Lets start out with some context. Why do
erythropoietic-stimulating agents or ESAs matter? Who exactly do they help?
DR. SARAH TOMASELLO:
ESA products are indicated for a variety of different types
of anemia, but particularly for anemia of chronic kidney disease because the
kidneys are responsible for producing the hormone erythropoietin and as kidney
function declines, the body is less able to produce this hormone and the need
for exogenous hormone is evident. So although we can use ESAs in other disease
state to help with anemia, kidney disease particularly rely on the exogenous
epoetin alpha or darbepoetin or whatever agent we are using.
DR. CHARLES TURCK:
How many patients in the US are impacted by ESAs?
DR. SARAH TOMASELLO:
Well the more recent prevalence data suggests that there is
about 20 million patients in the United States with some degree of chronic
kidney disease. The patients may develop anemia even in the most mild stages
of kidney disease which we would call stage 1 and stage 2, but usually it is
only a small percentage of patients what would be affected at that stage. The
biggest burden is the patients with more severe kidney disease and that is
estimated to be approximately 8 million people with stage III, IV, or V which
is the end-stage kidney disease.
DR. CHARLES TURCK:
Just to continue to define the scope of the problem. What
are some of the long-term complications of anemia in patients with chronic
kidney disease?
DR. SARAH TOMASELLO:
The most glaring would be probably in the area of quality of
life as well as increased risk for cardiovascular morbidity, mortality. Anemia
can effect every body system including cognition and exercise tolerance and
cause a lot of fatigue and decrease quality of life. Also anemia puts a
tremendous strain on the heart to work harder to profuse the body with oxygen.
So if you think about it as a patient is becoming more and more anemic, the
heart will try to compensate for the decreased oxygenation capacity and will
start to work harder to pump more blood causing eventually left ventricular
hypertrophy and potentially chronic heart disease in some patients. So it is
well known that patients with chronic kidney disease and anemia are at a higher
risk of cardiovascular morbidity, mortality and in fact, that is the number one
cause of death in patients who do live through dialysis which is end-stage
kidney disease.
DR. CHARLES TURCK:
So ESAs were introduced to the US market really just in the
last few decades. How was anemia of chronic kidney disease treated before
their advent?
DR. SARAH TOMASELLO:
The contrast is amazing. It is like night and day. The
first commercially available erythropoietic agent was epoetin alpha in this
country in 1989 and before that patients really were treated with transfusions
on red blood cells as well as androgen therapy using agents like testosterone
or fluoxymestrone to enhance erythropoiesis. Unfortunately, the side effects
of those agents were pretty severe and the scarcity of blood and infectious
complications as well as the risk of exposing patients to different antigens
from the transfusions would possibly preclude them from transplant later on.
So it was really kind of a nightmare.
DR. CHARLES TURCK:
How important is it for clinicians to ensure that patients
have repleted iron stores before starting ESA therapy.
DR. SARAH TOMASELLO:
It is essential. I would like an ESAs and iron to how your
car works. If you think about a car, you have gas in the gas tank or in this
model we would have iron in the gas tank and ESAs are like putting our foot
down on the gas pedal to speed up erythropoiesis and go forward. If you run
out of gas in the gas tank, it doesn’t matter how much you are stepping on the
accelerator. You are not going to go anywhere. Certainly, patients can still
maintain some amount of erythropoiesis with a minimal amount of iron, but if we
really wanted to optimize our ESA use and optimize erythropoiesis, we want to
make sure that the iron is available to the bone marrow and the iron stores are
also repleted.
DR. CHARLES TURCK:
So what sort of targets from an iron study's perspective
should clinicians be looking to hit, if we are starting ESA therapy.
DR. SARAH TOMASELLO:
The National Kidney Foundation KDOQI guidelines recommend
that the 2 parameters that are most important would be the TSAT which is the
transferrin saturation percent which is a marker of the iron that is available
to the bone marrow to be used readily for erythropoiesis and the ferritin which
is a marker not all that great marker, but it is a marker of our stored iron.
The iron that is sequestered in the reticula endothelial system waiting to be
mobilized and used if necessary. KDOQI recommends that the TSAT be maintained
between 20 to 50% and for patients who are not yet on hemodialysis, the
ferritin should be greater than 100 ng/mL and the patients who are on
hemodialysis, the ferritin should be greater than 200 ng/mL and this is because
patients on hemodialysis are losing blood every single time they have a
dialysis session. Some blood is lost in the tubing or microthrombi, so the
stores should be kept a little bit higher in those situations.
DR. CHARLES TURCK:
If you are just joining us, you are listening to Focus on
Pharmacy. I am your host, Dr. Charles Turck. Our guest is Dr. Sara Tomasello,
Clinical Associate Professor of the Ernest Mario School of Pharmacy at Rutgers,
The State University of New Jersey and a clinical specialist in nephrology at
Robert Wood Johnson University Hospital in New Brunswick, New Jersey. We are
discussing the role of erythropoietic stimulating agents or ESAs in anemia of
chronic kidney disease.
Dr. Tomasello are there any barriers to the accurate
interpretation of iron studies in the setting of ESA management in chronic
kidney disease?
DR. SARAH TOMASELLO:
Definitely, it is not an exact science. At this point, we
do use the transferrin saturation percent as I mentioned. Additionally the
KDOQI guidelines suggest using the hemoglobin content of reticulocytes or the
CHR as a better measure of actually how much iron is going into each new baby
red blood cell at the bone marrow. Unfortunately not all institutions have
these laboratory parameters available to them, so we may be still using the
TSAT instead of the CHR. The other problem is the ferritin. Ferritin is a
protein that may or may not bind to iron and is also an acute phase reactant.
So in a situation of inflammation or infection, ferritin is dumped into the
serum in response to this insult to the body and when you measure the serum
ferritin concentration, it may appear that you have tons of ferritin in the
serum, however, that ferritin is not indicative of the stored iron that is in
the reticula endothelial system, it is only a measure of the ferritin that
happens to be in the serum at that moment. So it can be very misleading and
typically when we are talking about the evaluation of iron studies, we must
take into account the clinical picture is the patient infected, do they have
some source of chronic inflammation that is causing their ferritin levels to be
high and that would suggest it may not be an indication of our iron stores, but
rather an acute process.
DR. CHARLES TURCK:
What are some other considerations that clinicians might
want to keep in mind when choosing a product for iron supplementation or repletion?
Are there any products in particular that you prefer over others in getting
patients to their goal TSAT levels?
DR. SARAH TOMASELLO:
When using the intravenous iron preparation, those are the
preferred preparations for patients on hemodialysis as we have consistent
intravenous access to give those agents. With the IV products, there are the
older products, iron dextran which is name brand either Dexferrum or INFeD and
then we have 2 newer products the iron sucrose or sodium ferric gluconate. The
2 older products that are iron dextran products have been associated with an
increased risk of anaphylactoid reactions or anaphylactic reactions and for
some time now have on to disuse because of the newer agents. They may still be
acceptable agents to use in certain circumstances; however, I think many
institutions have chosen the newer agents due to the decreased risk of these
adverse events. It is important with any of these agents, they have certain
infusion-related reactions if they are instilled too quickly, so instilling
them over a good amount of time may decrease the adverse reactions and in
general the 2 newer agents that I mentioned, iron sucrose and sodium ferric
gluconate are very well tolerated. There is concern that some of the
intravenous iron products may cause an inflammatory reaction and accelerate
processes like atherosclerosis. This is an area that is receiving a lot of attention;
a lot of research is being done to gain more knowledge about this possibility,
so I think we will hearing more about that in the near future.
DR. CHARLES TURCK:
How often should iron studies be monitored while the patient
is on ESAs?
DR. SARAH TOMASELLO:
The KDOQI guidelines recommend that for patients who are
receiving ESA therapy, if they are chronic hemodialysis patients, but not yet
on hemodialysis, the iron studies should be monitored quarterly. If they are
stable although there may be situations where more frequent monitoring would be
prudent situation where the hemoglobin is decreasing without an obvious cause
or dose change of the erythropoietic agents. For patients on hemodialysis,
generally speaking again probably more frequent monitoring is necessary if
their hemoglobins are not stable and otherwise we can monitor them every 3
months.
DR. CHARLES TURCK:
Now drawing upon your experience, how is it that you most
commonly see ESAs misused in clinical practice, is there anything that
clinicians tend to forget or fail to take into account when ordering or
prescribing ESA therapy.
DR. SARAH TOMASELLO:
In my practice, because I work at an acute care facility, I
see a lot of very sick patients who have a lot of reasons to be anemic besides
just chronic kidney disease. They may have blood loss from gastrointestinal
bleeding. They may have frequent phlebotomy because they are acutely ill. So
in my practice what I encounter a lot is escalating doses of ESA without
necessarily working up any other causes of the anemia and trying to correct any
modifiable causes of anemia. So for instance increasing the dose of the ESA
without obtaining iron studies or increasing the dose of ESAs without seeing if
the patient has B12 or folate deficiency. I think that is probably the most
common problem in my practice, it is just escalating doses without necessarily
trying anything else.
DR. CHARLES TURCK:
We have been speaking with Dr. Sarah Tomasello about the
role of ESAs and anemia of chronic kidney disease. Dr. Tomasello thank you so
much for joining us.
DR. SARAH TOMASELLO:
Thank you very much.
DR. CHARLES TURCK:
I am Dr. Charles Turck; you have been listening to Focus
on Pharmacy on ReachMD, The Channel for Medical Professionals. Be sure to
visit our web site at www.reachMD.com featuring on-demand pod casts of our
entire library and thank you for listening.
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