Anaemia means that not enough red blood
cells exist in the body. It is relatively common in CKD cats,
so it is important to know about it and to be prepared to deal with it.
Mild or moderate anaemia may be controlled using
various treatments which are discussed on the
Anaemia page. This page deals with a form of treatment
called erythropoiesis stimulating agents (ESAs), which are used for
severe non-regenerative anaemia caused by the CKD.
Treating anaemia in a CKD cat with an ESA when
appropriate is worthwhile.
ISFM consensus guidelines on the diagnosis and
management of feline chronic kidney disease (2016)
Sparkes AH, Caney S, Chalhoub S, Elliott J, Finch N, Gajanayake I,
Langston C, Lefebvre H, White J & Quimby J Journal of Feline Medicine
and
Surgery18 pp219-239 state "there is evidence that treatment
with erythrocyte-stimulating agents (ESAs) may improve quality of life and
potentially survival in some cats with CKD."
The University of Georgia College of Veterinary Medicine
has stated that anaemia is not necessarily a bad sign, because most
anaemic cats live for over 300 days, but many cats live a lot longer.
What are Erythropoiesis Stimulating Agents
The kidneys produce a hormone called
erythropoietin which stimulates the bone marrow to make red blood cells.
This process is known as erythropoiesis.
As the
kidneys fail in CKD, they cannot produce enough erythropoietin, so the
bone marrow is not stimulated, blood cells are not produced, and a
particular type of anaemia called
non-regenerative anaemia
results. Non-regenerative anaemia may have other causes (including other CKD-related problems such as uraemic
toxins), as discussed on the
Anaemia page, but this is the most common reason for it
in CKD cats.
Cats with mild anaemia (regenerative or non-regenerative) can be offered various treatments (see
the
Anaemia page). However, cats with severe non-regenerative anaemia
(PCV or HCT below 20%) caused by a lack of erythropoietin often
need artificial erythropoietin in order to control their anaemia. The
various forms of artificial erythropoietin are collectively known as erythropoiesis stimulating agents (ESAs). They are usually very effective,
and in fact one human study,
Anemia management and the delay of chronic renal
failure progression (2003) Rossert J, Fouqueray B & Boffa JJ Journal of
the American Society of Nephrology14
pp173-177 found that "treatment with epoetin may slow the
progressionof chronic kidney disease."
Unfortunately, after a
few months of use, a small percentage of cats may develop a reaction to
ESAs (commonly referred to on CKD support groups as the
antibody reaction,
but which in its worst form is known as pure red cell aplasia or PRCA)
which stops them working. However, this is by no means inevitable; with
the most commonly used ESA, darbepoetin (Aranesp), it only happens to 10%
of cats.
Types of Erythropoiesis Stimulating Agents
There are two categories of ESA which have been used in CKD cats:
Feline Erythropoietin
(rfEpo)
Feline erythropoietin has been developed in small quantities for use in
clinical trials.
There has also been a study into the feline erythropoietin gene.
Unfortunately, neither of these treatments is commercially available at present (June 2018),
and that is unlikely to change. There is a brief overview of these
treatments
below, but this page focuses
primarily on the treatments which are currently available for you to use, in
the form of human erythropoietin.
Human Erythropoietin
(rhEpo)
Since feline erythropoietin is not
commercially available, CKD cats in need of erythropoietin
supplementation will be using human
erythropoietin to enable their cat's bone marrow to continue to make red
blood cells.
There are a number of different types of
human erythropoietin available, as follows:
The main problem with the use of any human ESA in cats is that a small
percentage of cats develop an antibody reaction to the
treatment. This is discussed
below and
is not as gruesome as it sounds, but obviously it is something you want to
avoid if at all possible.
Epoetin alfa was the subject of the first study into the use of ESAs in
cats back in 1998, and has been used in CKD cats for many
years (I used it myself for Thomas in 1999). However, these days darbepoetin (Aranesp),
which has been the subject
of more feline studies, is the treatment of choice at US vet schools,
primarily because it is the ESA which is least likely to cause the antibody
reaction.
ISFM consensus guidelines on the diagnosis and
management of feline chronic kidney disease (2016)
Sparkes AH, Caney S, Chalhoub S, Elliott J, Finch N, Gajanayake I,
Langston C, Lefebvre H, White J & Quimby J Journal of Feline Medicine &
Surgery18 pp219-239 state "the use of darbepoetin alfa is
preferred over epoetin alfa as it appears significantly less likely to
induce PRCA."
I think darbepoetin (Aranesp) is the best choice and is what I would
choose to use for my own cats. However, if you cannot afford darbepoetin
(it costs more upfront) or if your cat's need is urgent and you can obtain
one of the other ESAs more quickly, you could consider using one of the other
ESAs.
You can always switch to darbepoetin later.
If you have already started another ESA but would like to switch to
darbepoetin, read how to do this
here.
When to Use Erythropoiesis
Stimulating Agents
A small number of vets seem to rush to use ESAs as soon as a cat is diagnosed with
anaemia, even if the cat is barely anaemic. The majority, however, seem to be
reluctant to use ESAs because of the risk of an
antibody reaction. In my opinion, neither of
these responses is appropriate.
Depending upon the severity,
type and cause of the anaemia, there are other treatments which may be
more suitable for your cat and which are certainly cheaper. See the
Anaemia
page for more information. In some cases, however, an ESA is an
appropriate choice. There are a number of factors to consider:
General Criteria
The cat should have
non-regenerative anaemia
caused by a lack of erythropoietin. A reticulocyte test can confirm
that the anaemia is non-regenerative, but this test is only accurate if
the PCV or HCT has been below 20% for five days or longer; and it does not
confirm that the cause is a lack of erythropoietin.
The PCV or HCT should not have fallen suddenly, e.g.
from 24% one week to 17% the next. Most cats with anaemia
caused by CKD become anaemic gradually which means their bodies have had
time to adapt to it to some degree.
A sudden fall in PCV for a cat in IV fluids is slightly different: PCV may fall quite a lot in cats on IV fluids, who are usually dehydrated
when first placed on a drip, which makes the PCV level look artificially high. The PCV level once the cat is properly hydrated is
therefore the more accurate reading. However, if your cat develops sudden, severe anaemia but
has not been on IV fluids, ask your vet to check for
other causes
of anaemia. One common cause in such cases is
gastrointestinal bleeding.
Usually (but not always, particularly in older cats) the CKD will be relatively advanced, with creatinine over 5
mg/dl (US) or 450 µmol/L (international), at least at initial diagnosis. This indicates that the
kidney damage is probably more severe, and therefore the kidneys are
unlikely to be producing sufficient erythropoietin on their own.
Thomas actually needed an ESA regularly when his creatinine level was only 3.57
mg/dl (USA) or 316 µmol/L (international), but his creatinine level had
been a lot higher at initial diagnosis.
Severity of Anaemia and
Symptoms
Assuming the anaemia is indeed non-regenerative anaemia
caused by a lack of erythropoietin, you then need to consider how severe
the anaemia is:
Managing anemia in patients with chronic kidney
disease (2011) Chalhoub S, Langston CE Veterinary MedicineMay 2011 mentions that the Animal Medical Center in NYC considers a
PCV below 20% to be the level at which treatment with an ESA should be considered.
Some experts believe how the cat is acting and feeling are also important.
In
Chronic kidney disease (CKD) in dogs and cats -
staging and management strategies (2015) A Presentation to the
Virginia Veterinary Medical Association 2015 Virginia Veterinary
Conference, Dr D Chew states "Therapy may be started in
symptomatic animals with PCV values < 20% if clinical signs of
anemia are present and problematic."
ISFM consensus guidelines on the diagnosis and
management of feline chronic kidney disease (2016)
Sparkes AH, Caney S, Chalhoub S, Elliott J, Finch N, Gajanayake I,
Langston C, Lefebvre H, White J & Quimby J Journal of Feline Medicine &
Surgery18 pp219-239 goes further, stating "ESA therapy should be considered in
cats with persistent CKD-associated anaemia that is symptomatic; or if the
PCV is persistently <20%."
Summary
If your cat has a PCV level below 20% which has not developed
suddenly, and/or if your cat has signs of severe anaemia, such as
breathlessness, lethargy or severe loss of appetite, you should talk to
your vet about starting an ESA.
Ideally your vet will have been able to check that your cat has
non-regenerative anaemia via a reticulocyte test, but I would not wait the
necessary five days to do this if your cat is very sick, especially
if your cat's CKD is relatively advanced (creatinine over 5 mg/dl (US) or
450 µmol/L (international)).
There are a number of different types of human
erythropoietin available. You can read about the pros and cons of each one
and how to measure and dose them under their individual categories. There
are also some important usage guidelines applicable to all ESAs, including
information on correct storage and possible side effects.
Aranesp (darbepoetin alfa) is
made by Amgen. It is an erythropoiesis stimulating protein (so it is
slightly different to the other ESAs which are all recombinant human
erythropoietins or rhEpo), and contains five N-linked
oligosaccharide (carbohydrate) chains rather than three. This is supposed
to give it greater metabolic stability, and may be why it is less likely
to cause the antibody reaction.
Darbepoetin alfa: a new therapy for the
management of anaemia associated with chronic kidney disease
(2002) Lindberg J Expert Opinion on Biological
Therapy
2(8) pp977-84 discusses the use of darbepoetin alfa in human patients.
In 2005 a number of US veterinary schools,
including North Carolina State University, University of Penn, Animal
Medical Center in New York, University of California at Davis, and the
University of California Veterinary Medical Center (UCVMC), began using
darbepoetin alfa on an informal basis.
By 2010 darbepoetin had been used on approximately
50-60 cats at UCVMC, with favourable results. As a result, UCVMC now tends
to use darbepoetin as a first line treatment for most cats (except when they
expect the need for an ESA to be short-lived because the cat is an acute
case, in which case they may use epoetin alfa (Epogen) instead since it
may show a quicker response time). The Animal Medical Center in NYC also
uses darbepoetin
as a first line treatment, and has found the
antibody rate to be around
10%.
Managing anemia in patients with chronic kidney
disease
(2011) Chalhoub S, Langston CE Veterinary MedicineMay 2011discusses
AMC's experiences with darbepoetin.
There are two formulations of darbepoetin alfa, one
containing human albumin, and one without human albumin and known as HSA-free. The HSA-free form
of Eprex (a type of epoetin alfa available in Europe) had a higher
antibody reaction rate. I do not know if this is also likely to be true
for darbepoetin but it is a possibility. However, some vets feel that
ESAs
containing albumin may also carry an increased risk of an adverse
reaction, since the albumin is a human product. It now appears that
the only version which is widely available in the USA is the HSA-free
version, because humans apparently had a lower reaction to this, so in
practice this is probably what you will be offered. I would not worry too
much about this.
Although darbepoetin is probably the best choice, certainly from the antibody
reaction perspective, there are a few
possible downsides to be aware of:
It costs a lot more than epoetin alfa (Epogen or Eprex). It needs to be given less
frequently, so the cost should even out over time, but the initial outlay
will be much higher, which is a concern for many people.
It may take longer to start taking effect. This is not the case for all
cats, but it could be a problem if your
cat's anaemia is particularly severe and you want to start making a
difference as quickly as you can.
It can be hard to work out the best dose for an individual cat so there
are a number of different protocols Some cats
respond too well to Aranesp, which carries risks too.
Although I myself used epoetin alfa in the form of Eprex for Thomas,
I think overall darbepoetin is the best choice and is what I would choose
to use for my cats these days. However, if cost is a factor, or if your cat has critically
severe anaemis and you can obtain one of the other ESAs more quickly,
then I would consider using that instead.
If you have already started another ESA but would like to switch to
Aranesp, read how to do this
here.
Darbepoetin Alfa (Aranesp): What
and Where
to Buy
Some vets think ESAs cost a fortune and therefore may not
bother to prescribe them. However, if you know where to look, it is usually possible to obtain these products
at more reasonable prices..
Even if you do not need to use ESAs at the moment, I would suggest you
read below on how and where to obtain them, especially if your cat is
anaemic, so you can obtain one quickly should your cat's anaemia worsen to
the point where you need to use one.
Darbepoetin is more expensive than epoetin alfa; but since
you need to use it less frequently, over time the price difference is not as bad as
it appears.
Because it is a human medication, there are a number of different
strengths of darbepoetin available, so make sure you buy the correct size
for your cat (see below).
It is sold as a single use human medication, but the single
use sizes for humans are routinely used for multiple doses in veterinary
medicine.
Darbepoetin Alfa (Aranesp):
What and Where to Buy USA
For cats you need the 25mcg/ml vial size. This size of vial
contains approximately 6-10 feline doses, depending upon the size of your
cat and which dosing regimen you use. However, since it does not need to
be administered as frequently as epoetin alfa (Epogen), the cost should
work out about the same overall. You will need a prescription from your
vet.
Your upfront cost will be around US$200-250 for a vial, which (depending
upon the dose used and your cat's size) should work out at a rough cost of around US$25-50 a
week initially, reducing to US$25-50 every 3-4 weeks as your cat
stabilises.
It is usually easier to obtain price quotations if you have the NDC
(National Drug Code) for the products you are interested in:
Single vial of Aranesp
25mcg/ml: NDC 55513-002-01
Pack of four vials of Aranesp
25mcg/ml: NDC 55513-002-04
You will usually also need U100 insulin 0.3 or 0.5cc syringes which you
use to draw the darbepoetin from the vial in cat-sized doses. You can obtain
insulin syringes from your local pharmacy (you will need a prescription).
Buying Darbepoetin From Local Pharmacies
You could try using a discount card. Sadly not many pharmacies
seem to accept discount cards for ESAs, but you can definitely use the
Walgreens Prescription Savings Club card, see below. See Cheap Supplies
Local USA
for information on other
discount cards.
Some local pharmacies in the USA can order Aranesp
with overnight delivery for around US$220-250 per 25 mcg vial. Hospital
pharmacies often have darbepoetin (Aranesp) in stock and may well be prepared to sell it
to you with a prescription.
Walgreens
Walgreens can usually obtain darbepoetin
(Aranesp) for you overnight at a reasonable price. The procedure is as follows:
Visit or call your local Walgreens (if you visit, take
your cat's prescription with you). Try to speak to a pharmacist rather
than a clerk if possible - apparently the pharmacist has access to the
full catalogue whereas the clerks often do not.
It is particularly important to explain that you wish to order the
darbepoetin - most branches do not hold this product in stock, but
instead order it from the Walgreens Specialty Pharmacy, but not every employee realises this.
It greatly increases your chances of success if you
can provide the pharmacist with the NDC (National Drug Code). The NDC
for a single vial of Aranesp
25mcg/ml is 55513-002-01 (the code for a pack of
four is above).
It may be worth trying to use a discount card.
Most of these cards are free but they may give you a lower price
(though this is more often the case with fluids than ESAs). It is worth
a try anyway. Many people print out all of these
cards, then ask the pharmacist to check which one gives them the biggest
discount and use that.
You can definitely get a discount if your cat joins the Walgreen's discount scheme, the
Prescription Savings Club.
You can do this online or
in the store. This costs US$35 a year
for family membership, which includes cats (if you already have a
family membership, you can add your cat to it for free),
or US$20 a year for an individual (i.e. your cat). Unfortunately this is
not available if you live in Washington State.
The full price is US$255, but if you join
the Prescription Savings Club, one
vial costs US$190.99 (July 2018),
plus the cost of club membership the
first time you order it.
If you live in Florida, there is a new programme
called
Walgreens Plus,
available at 17 stores. According to the
price list dated March 2018,
under this scheme one
vial also costs US$190.99,
plus the cost of club membership the
first time you order it.
Ask the pharmacist to order the ESA
(and suitable syringes, if you need them and have a prescription for
them)
for you. You may
find that the branch you try is reluctant to sell one vial only. In such
cases, quote the NDC code for one vial again, or try another branch, or ask to speak to the head
pharmacist; or, if your need is not urgent, return another day when with
luck a more helpful person will be available.
Wait for it to arrive (it is usually available for
next day delivery) and go and collect it. Remember to place it in the
fridge as soon as you get home.
Buying Darbepoetin Online
If there is no Walgreens nearby, you may
need to order
online. The downside is that the cheapest online supplier (Walmart
Specialty Pharmacy) may take up to a week to ship the first time you place
an order. Also, some online retailers (not those mentioned here) insist you buy at
least four vials, which cost US$750 or more.
Darbepoetin must be kept cold, so overnight
chilled shipping is necessary.
Sells
darbepoetin (Aranesp) for
around US$210-215 per 25mcg/ml vial including overnight refrigerated shipping,
syringes and often a sharps container.
The website does not show prices so this is the approximate price but for
reference, one member of Tanya’s Support Group paid US$212.27 in April 2018
for the Aranesp, overnight shipping, syringes and a sharps container.
Note: this is Walmart Specialty
Pharmacy, which deals with complex therapies such as ESAs. You must use
the link given above or the dedicated phone number (1-877-453-4566) to get
these prices, which are not available at the standard online Walmart
pharmacy, and are unlikely to be available at your local Walmart
Pharmacy.
The first time
you order it will take around a week to complete the registration process.
Walmart will contact you to ask for your preferred delivery date, so you
can be sure you are there to receive your order. If you prefer, it can be
shipped to your local Walmart pharmacy for you to collect. If you opt for
this, ask them to ensure that your local pharmacy will keep it chilled
until you can collect it
Sell darbepoetin (Aranesp) for US$249.95 a vial or US$240
per vial if you buy four vials, plus the cost of chilled shipping (around
US$15-25 depending upon where you live). They
normally ship overnight, but if your need is urgent, call them first to
check they have it in stock.
Darbepoetin Alfa (Aranesp): What and Where to
Buy UK
In the UK you would normally choose the 20mcg/0.5ml prefilled syringes for
a cat.
Although Eprex appears to be a lot cheaper, since
Aranesp does not need to be administered as frequently, the cost should
work out about the same overall. The price varies depending upon your
source, but (depending upon the dose used and your cat's size) t should
work out roughly at a cost of around Ł5-10 a week initially, reducing to
Ł5-10 every 3-4 weeks as your cat stabilises. Aranesp must be kept cold,
so overnight chilled shipping is necessary if you buy online.
Unfortunately,
UK vets are now allowed to charge to write you a prescription to
use elsewhere. My vet charges
Ł12.50. If
your vet does this, make sure your prescription is a repeat one so you
don't have to pay for a new prescription every month or so.
Sells four 20mcg/0.5ml prefilled
syringes for Ł180 inc VAT and shipping (I do not know if they ship chilled
as they should). Apparently they will also ship to some other EU
countries. Check with your vet whether this syringe formulation is
suitable and whether the product will be shipped chilled.
You can also
ask your local chemist if they can help (Lloyds Pharmacy was able to order
Eprex for me, and I imagine they could order Aranesp too). Your vet may also be able to
order it for you. It can also be worth checking with your local hospital
pharmacy, which may be able to help more quickly and at a reasonable
price.
Aranesp must be kept cold, so overnight
chilled shipping is necessary.
Darbepoetin Alfa (Aranesp): What and Where to Buy Canada
In Canada you would normally choose the 20mcg/0.5ml prefilled syringes or
the 25mcg/0.4ml vials for a cat.
There are a number of possible dosing protocols for
darbepoetin, as shown below. Remember, darbepoetin is given less frequently than
epoetin alfa or epoetin beta, usually only once a week to start with.
Because darbepoetin is given less frequently
than epoetin alfa or epoetin beta, it may also take longer
to take effect for some cats. Therefore, if your cat
has very severe anaemia before starting darbepoetin (e.g. PCV below 15%), you may need to consider
a
blood transfusion
to tide your cat over until the darbepoetin begins to work. Some
people whose cat's PCV is low (e.g. 15-17%) use epoetin alfa to start with
because in principle it takes effect more quickly, and then they switch to
darbepoetin later. There is information on this
here.
Always check PCV
before you give the next shot in case your cat is particularly
responsive.
If your cat's PCV does rise too quickly (more
than a 3% increase in PCV or HCT per week), ask your vet about reducing
the dose or giving the darbepoetin less frequently. If your cat's PCV does
not seem to be rising, click
here for tips on what to do.
Overall it appears that many cats respond well to darbepoetin, and in some
cases their PCV rises too quickly. It may therefore be better to start with a
low dose, particularly if your cat is
small; but be guided by your vet. It
is important to adapt the dosing schedule to what works for your cat.
Recommendation
Cat Weight
Source
Dosage
5 lb
2.27 kg
7.5 lbs
3.4 kg
10 lb
4.5 kg
12.5 lbs
5.7kg
Plumb's (2011)1
0.45 mcg
per kg* of cat
1.0 mcg
1.5 mcg
2.0 mcg
2.56 mcg
Dr DiBartola
0.25-0.5 mcg
per kg of cat
0.57-1.14 mcg
0.85-1.7 mcg
1.125-2.25 mcg
1.425-2.85 mcg
Animal Medical Center, NYC2
1 mcg
per kg of cat
2.27 mcg
3.4 mcg
4.5 mcg
5.7 mcg
ISFM3
1 mcg
per kg of cat
2.27 mcg
3.4 mcg
4.5 mcg
5.70 mcg
UC Davis4
6.25 mcg per cat
6.25 mcg
6.25mcg
6.25mcg
6.25 mcg
Total Range
0.25-1 mcg
0.57 -6.25 mcg
0.85-6.25 mcg
1.125-6.25 mcg
1.425-6.25 mcg
*A kg is 2.2 lbs
1The dose recommended by
Plumb's Veterinary Drug Handbook
(7th edition) (2011) is the same as the recommended
dose for human patients on darbepoetin.
2Anaemia
of renal disease: what is it, what to do and what's new (2011) Chalhoub S, Langston C & Eatroff A
Journal of Feline Medicine & Surgery13(9) pp629-40
states that this dosage is used at the
Animal Medical Center in NYC because 62% of cats
in their database responded to this dose when it was given once weekly, whereas
only 12% responded to a dose of 0.45 mcg/kg once weekly.
4Those giving the same dose to every cat
regardless of weight, such as the University of California at
Davis, usually give 6.25 mcg along
with iron in the first week, but then space the Aranesp out as far as
possible, usually giving it once every 2-4 weeks. I have heard
from a number of people who found their cat's PCV increased too
quickly on this dose.
I have also heard from a couple of people
who gave their cats
5 mcg subcutaneously each week. Again, one of these cats had a PCV
that was increasing rather quickly.
Personally, I think I would start with the
1 mcg per kg of cat dosing protocol, as seen in The Animal Medical
Center and ISFM rows in the above table.
Remember, these are starting doses.
Please read below for maintenance doses. Also see below for how to
measure
the darbepoetin and how to
administer it.
Darbepoetin Alfa (Aranesp): How to
Measure
Because it is a human medication, darbepoetin needs to be divided into
cat-sized doses. If you are giving darbepoetin at home (as many people
do), you will need to learn how to do this yourself. It's best to let
your vet measure the dose the first time and show you how to do it.
They can also show you how to inject it. However, here is a quick
guide in case you forget.
USA
You will normally purchase the
25mcg/ml vial size.
In other words, your vial contains one ml of liquid, which contains 25
mcg of darbepoetin.
Let's take the example of a 10lb cat who is being given 1 mcg of
darbepoetin per kg of cat. If you check the table above, you will see
that a 10lb cat weighs 4.5kg, so this cat needs 4.5 mcg each time:
Your vial contains 25 mcg, so it contains 5.5 doses altogether (25mcg
divided by 4.5mcg).
You have one ml of liquid in your vial, so you need to divide this by
5.5 (the number of doses it contains altogether), which results in
0.18 ml. Therefore you need to withdraw a little under 0.20ml (20% or one
fifth) of the medication each time you give it.
Most people do this using an insulin syringe.
Instructions for use is an
instruction leaflet from Amgen, the manufacturer of Aranesp, which
explains how to draw Aranesp from the vial.
You will
need syringes to draw and give the medication. Most people use human insulin
syringes. These are sold as U100 syringes, which means there are 100
units in 1 ml. They are usually available in three sizes, 1 ml (100
units), 0.5ml (50 units) or 0.3 ml (30 units), and most people use 0.5
or 0.3 ml syringes for cats (see
above for
sources). Unfortunately, insulin units are
not the same as Aranesp units so working out the dose can be confusing.
As a general guide, one insulin unit is 0.01ml; so
each unit on an insulin syringe is 0.01ml; but the safest thing is to
ask your vet to measure out the doses for you and show you how much
you need to give.
Although the leaflet mentions that Aranesp
should only be used once, because cats need tiny doses and Aranesp is
expensive, most people re-use the vial with no problems, as long as
they store it properly (see
below).
UK
You will normally purchase the 20mcg/0.5ml size syringe.
In other words, your syringe contains 0.5ml of liquid, which contains
20 mcg of darbepoetin.
Let's take the example of a 10lb cat who is being given 1 mcg of
darbepoetin per kg of cat. If you check the table above, you will see
that a 10lb cat weighs 4.5kg, so this cat needs 4.5 mcg each time.
Your syringe contains 20mcg, so it contains around 4.5 doses
altogether (20mcg divided by 4.5mcg).
You have 0.5 ml of liquid in your syringe, so you need to divide this by
4.5, which results in 0.11 ml. Therefore you need to withdraw a little
over 10% or one tenth of your medication each time you give it.
Ask your vet for the best way to remove what you need from the
syringe. You may need to attach a needle to it and give the required
amount, then remove the needle and use a new needle the next time you
give it. Alternatively,
you may have to transfer the contents into a sterile
container, which is not exactly easy. The usual method with Eprex,
which also comes in syringes, seems to be to
transfer the contents to an empty sterile vial, and measure it from
there with a small insulin syringe.
Instructions for use is an
instruction leaflet from Amgen, the manufacturer of Aranesp, which
explains how to draw Aranesp from a vial.
If you do this, you will
need syringes to draw and give the medication. Most people use human insulin
syringes. These are sold as U100 syringes, which means there are 100
units in 1 ml. They are usually available in three sizes, 1 ml (100
units), 0.5ml (50 units) or 0.3 ml (30 units), and most people use 0.5
or 0.3 ml syringes for cats (ask your vet for some). Unfortunately, insulin units are not the same as Aranesp units so working out the dose can be confusing.
As a general guide, one insulin unit is 0.01ml; so
each unit on an insulin syringe is 0.01ml; but the safest thing is to
ask your vet to measure out the doses for you and show you how much
you need to give.
Although the leaflet mentions that Aranesp
should only be used once, because cats need tiny doses and Aranesp is
expensive, most people re-use the vial with no problems, as long as
they store it properly (see
below).
Darbepoetin Alfa (Aranesp):
Maintenance Dosage
It is very important to check your cat's PCV level
before you give a dose of darbepoetin, in case your cat's PCV is rising faster than expected.
ISFM consensus guidelines on the diagnosis and
management of feline chronic kidney disease (2016)
Sparkes AH, Caney S, Chalhoub S, Elliott J, Finch N, Gajanayake I,
Langston C, Lefebvre H, White J & Quimby J Journal of Feline Medicine &
Surgery18 pp219-239 state that once target PCV is reached, the
suggested maintenance dose is either the same dose (1 mcg per kg body
weight) given every 2-3 weeks or a reduced dose of 0.5 mcg per kg body weight once weekly,
depending upon the cat's PCV levels.
's recommendation once target PCV is
reached is "decreasing the frequency of administration to every two or
three weeks." They go on to say "Once an administration frequency of every three weeks is
achieved, we lower the dose to 0.45 μg/kg every three weeks or the
lowest dose that maintains an adequate PCV."
Darbepoetin Alfa (Aranesp):
Dosage When Switching From Another ESA
Some people start off by giving
epoetin alfa to their
cat, because their cat has very severe anaemia and epoetin alfa tends to work
faster than darbepoetin. Once their cat's anaemia is less severe, they may
wish to switch to darbepoetin.
Other people may start with epoetin alfa (Epogen, Procrit or Eprex) because that is what
their vet offers or what they can obtain quickly, but they then decide to
switch to darbepoetin
because they wish to reduce the risk of the antibody reaction. This
section explains how do to this. However, if you wish to switch from
another ESA to Aranesp because you think your cat has developed the
antibody reaction to the other ESA, please read
here.
In
Anemia of chronic kidney disease
(2009)
CVC in San Diego Proceedings Dr CL Langston
states
"For patients
being converted from rHuEPO therapy, 200 U of rHuEPO is equivalent to 1 µg
of darbepoetin."
Plumb's Veterinary Drug Handbook
(7th edition) (2011)
similarly states that you can convert the dosage by
dividing the total weekly number of Epogen or Procrit units by 200. This
will then give you the equivalent weekly dose of Aranesp.
For example, a 10 lb (4.5kg) cat would typically receive
450 units of Epogen three times a week, so the weekly total is 1350. Divide the 1350 by 200 and you get
6.75, so the cat would receive 6.75mcg of Aranesp once a week. If you look
at the suggested dosages in the table above, this is a relatively high dose
for a 10lb (4.5kg) cat.
Be guided by your vet.
Darbepoetin
Alfa (Aranesp) Usage Guidelines
Please see the additional usage guidelines
below which apply
to all ESAs.
This is the
same product as Epogen and is also made by Amgen, but it is sold by Ortho Biotech in the
USA for the treatment of anaemia in human CKD patients who are not on
dialysis. It is also commonly used for cancer patients with anaemia caused
by chemotherapy.
This is the version of epoetin alfa made
by Janssen-Cilag in Europe for the treatment of
anaemia in both dialysis and non-dialysis human patients. It is also used for
human
patients with anaemia from other causes, such as chemotherapy. Whilst
Eprex is a form of epoetin alfa, it is not identical to Epogen/Procrit.
Epogen and Procrit have been used in CKD cats
in the USA for
many years. Epogen was the subject
of a clinical trial,
Use of recombinant human erythropoietin for
management of anaemia in dogs and cats with renal failure
(1998)Cowgill LD, James KM, Levy JK, Egrie JC, Browne JK,
Miller A, Lobinger R Journal of the American Veterinary
Medical Association212 pp521-8), in which the antibody reaction was seen in 5
out of 7 cats treated with Epogen for more than six months. The dosing
schedule used was very different to that described below, and in other
research by some of the same researchers, the rate was found to be lower.
One of the researchers has advised me that in her experience, the rate for
the antibody reaction tends to be around 30%.
Eprex has been used in CKD cats in the UK for many years - I myself used it
for Thomas in 1999 with no problems.
Erythropoietin-associated PRCA: still an unsolved
mystery (2006) Schellekens H, Jiskoot W Journal of
Immunotoxicology3(3) pp123-130 explains that the currently
available HSA-free form of Eprex, which contains polysorbate 80 instead of
albumin in order to comply with European regulations, had a higher
antibody reaction rate.
Epoetin Alfa (Epogen, Procrit or Eprex): What
and Where
to Buy
Some vets think ESAs cost a fortune and therefore may not
bother to prescribe them. However, if you know where to look, it is usually possible to obtain these products
at more reasonable prices..
Even if you do not need to use ESAs at the moment, I would suggest you
read below on how and where to obtain them, especially if your cat is
anaemic, so you can obtain one quickly should your cat's anaemia worsen to
the point where you need to use one.
Epoetin alfa is sold as a single use human medication, but
the single use sizes are routinely used for multiple doses in veterinary
medicine.
Epoetin Alfa (Epogen or Procrit): What and Where to Buy
USA
Most people
use the 2,000 iu/Ml strength of Epogen. You may be able to use the 3000
iu/Ml or 4000 iu/Ml strengths at a pinch if your cat is on the bigger
side, but you definitely do not want the 10,000 iu/Ml and
higher strengths, because it is too difficult to obtain cat-sized doses
from these.
The 2000 iu/Ml strength vial contains
approximately 4-8 feline doses, depending upon the size of your cat. You will need a prescription from your vet. Your upfront cost will be around US$50 for a vial (or around US$135 for
four), which (depending upon the dose used and your cat's size) should
work out at an initial weekly cost to use of around US$25-50 a
week initially, reducing to US$25-50 every 3-4 weeks as your cat
stabilises.
You will usually also need U100 insulin 0.3 or 0.5cc syringes which you use to draw the
Epogen or Procrit from the vial in cat-sized
doses. You can
obtain insulin syringes from your local pharmacy (you will need a
prescription).
Buying Epogen or Procrit Locally
You could try using
a discount card. Sadly not many pharmacies
seem to accept discount cards for ESAs, but you can definitely use the
Walgreens Prescription Savings Club card, see below. See
Cheap Supplies
Local USA for information on other
discount cards.
Some local
pharmacies in the USA can order Epogen or Procrit
with overnight delivery for around US$40-50 per 2000 iu/Ml vial. Hospital
pharmacies often have Aranesp in stock and may well be prepared to sell it
to you with a prescription.
Walgreens
Walgreens can usually obtain epoetin alfa
(Epogen) for you overnight at a good price, though it appears you may have
to buy a minimum of four vials (individual pharmacists may be prepared to
sell you one vial). The procedure is as follows:
Visit or call your local Walgreens (if you visit, take
your cat's prescription with you). Try to speak to a pharmacist rather
than a clerk if possible - apparently the pharmacist has access to the
full catalogue whereas the clerks often do not.
It is particularly important to explain that you wish to order the
epoetin alfa - most branches do not hold this product in stock, but
instead order it from the Walgreens Specialty Pharmacy, but not every employee realises this.
It may be worth trying to use a discount card.
Most of these cards are free but they may give you a lower price
(though this is more often the case with fluids than ESAs). It is worth
a try anyway. Many people print out all of these
cards, then ask the pharmacist to check which one gives them the biggest
discount and use that.
You can definitely get a discount if your cat joins the Walgreen's discount scheme, the
Prescription Savings Club.
You can do this online or
in the store. This costs US$35 a year
for family membership, which includes cats (if you already have a
family membership, you can add your cat to it for free),
or US$20 a year for an individual (i.e. your cat). Unfortunately this is
not available if you live in Washington State.
If you join the Prescription Savings
Club, four
vials cost US$135.96 (July 2018).
You can also buy Procrit for US$53.49 per vial.
If you live in Florida, there is a new programme
called
Walgreens Plus,
available at 17 stores. According to the
price list dated March 2018,
under this scheme four
vials also costs US$135.96,
plus the cost of club membership the
first time you order it.
Ask the pharmacist to order the ESA
(and suitable syringes, if you need them and have a prescription for
them)
for you. You may find
that the branch you try is reluctant to sell one vial only. In such
cases, quote the NDC code for one vial again, or try another branch, or ask to speak to the head
pharmacist, or if your need is not urgent, return another day when with
luck a more helpful person will be available.
Wait for it to arrive (it is usually available for
next day delivery) and go and collect it. Remember to place it in the fridge as soon as you get
home.
ells Epogen
for around US$50 per 2,000 iu vial, including
overnight refrigerated shipping, syringes and often a sharps container.
The website does not show prices so this is the approximate price but for
reference, a member of Tanya’s Support Group paid US$50 in September 2015
for Epogen, overnight shipping and syringes, whilst another member paid
only US$36 in December 2016 for Epogen and overnight shipping.
Note: this is Walmart Specialty
Pharmacy, which deals with complex therapies such as ESAs. You must use
the link given above or the dedicated phone number (1-877-453-4566) to get
these prices, which are not available at the standard online Walmart
pharmacy, and are unlikely to be available at your local Walmart
Pharmacy.
The only real downside is that it can
take around a week to complete the registration process the first time you
order. Walmart will contact you to ask for your preferred delivery date,
so you can be sure you are there to receive your order. If you prefer, it
can be shipped to your local Walmart pharmacy for you to collect. If you
opt for this, ask them to ensure that your local pharmacy will keep it chilled.
Sell Epogen for US$59.95 for a 2000 iu vial or US$55
per vial if you buy five vials or US$50 per vial if you buy ten. You also
have to pay the cost of chilled shipping (around
US$15-25 depending upon where you live). They
normally ship overnight, but if your need is urgent, call them first to
check they have it in stock.
Epoetin Alfa (Eprex): Where to Buy UK
Eprex is available in various strengths but you do not want
the 10,000iu/ml and higher strengths, because it is too hard to obtain
cat-sized doses from these.
You will usually be offered the 1,000iu/0.5ml
strength, which confusingly is the same as the 2,000iu/mL strength, but half
the amount. Your vet should be able to advise you on which strength to
buy.
The 1000 iu/0.5mL strength vial contains
approximately 2-4 feline doses, depending upon the size of your cat. You will need a prescription from your vet.
Eprex is available from chemists, although you will need a
prescription from your vet, and the chemist may have to order it in for
you (usually it can be delivered in a day or two). In April 2011 Boots
gave me a quote for 12 vials of
1000 iu/0.5mL Eprex of Ł107.51, but
needed five working days to get them. Lloyds Pharmacy told me they
could only get the 2000 iu/0.5mL strength, for around Ł100
for six vials, but didn't know the timeframe.
The best thing to do is to call pharmacies in your neighbourhood to check
prices and delivery timeframes. One lady wrote to tell me that she was able to obtain Eprex
very quickly from her local hospital pharmacy.
Epoetin Alfa (Eprex): Where to Buy Canada
Eprex is available in various strengths but you do not want
the 10,000 iu/ml and higher strengths, because it is too hard to obtain
cat-sized doses from these.
You will usually be offered the 1,000 iu/0.5mL
strength, which confusingly is the same as the 2,000iu/mL strength, but half
the amount. Your vet should be able to advise you on which strength to
buy.
Sells six vials of 1000 iu/0.5mL strength Eprex for around CA$110
(2015).
Eprex should also be available from local
pharmacies, particularly hospital pharmacies. In November 2011, one
person in the Toronto area was able to obtain six vials
1000 iu/0.5mL strength Eprex from her local pharmacy
for CAN$119. In November 2014 one person was able to obtain six vials of
the 4000 iu strength for CAN$400.
Epoetin alfa (Eprex): Where to Buy Australia
Your best bet is probably a hospital pharmacy, with a prescription from
your vet.
Plumb's Veterinary Drug Handbook used to
recommend a higher starting dose for cats with severe anaemia, i.e. for cats with a PCV level below 14%, the 2008 edition of Plumb's suggested using up to
145 units per kg (2.2lbs) of bodyweight subcutaneously three times a
week.
Plumb's also
used to suggest that
a lower dose of 48.4
units per kg (2.2lbs) of cat, given subcutaneously three times a week,
might be advisable for cats with
hypertension (high
blood pressure) before starting epoetin alfa, or if
hypertension appears after starting. Neither of these recommendations
appear in the 2011 edition of Plumb's.
Talk to your vet about the best approach
for your cat.
When giving the ESA three times a week, I would simply give it every
other day with one day left over e.g. Mon/Wed/Fri or Tue/Thur/Sat. It is very important to check your cat's PCV once
each week and before you
give that day's dose, in case your
cat's PCV is rising faster than expected.
The exact amount to be given depends upon
the strength which you are using. These medications are sold in
varying strengths, but the larger sizes (10,000iu/mL upwards) are
impossible to give in cat-sized amounts, so try to use nothing larger
than the 3000iu/mL strength.
Most people in the USA use the 2000iu/1ml strength,
whilst most people in the UK use the 1000iu/0.5mL strength.
If Standard Dosage of 100 units per kg in Weight is Prescribed
Cat Weight
5 lb
2.27 kg
7.5
lb
3.4 kg
10 lb
4.5 kg
12 lb
5.45kg
Epoetin alfa Strength
Needs
227 units
Needs
340 units
Needs
450 units
Needs
545 units
1000 iu/0.5 ml*
0.113 ml
0.1835 ml
0.225 ml
0.273 ml
2000 iu/1ml*
0.113 ml
0.1835 ml
0.225 ml
0.273 ml
3000 iu/1ml
0.075 ml
0.122 ml
0.15 ml
0.18 ml
4000 iu/1ml
0.056 ml
0.09 ml
0.1125 ml
0.137 ml
*The 1000iu strength contains 1000iu
but in 0.5mL so it is the same strength as the 2000iu/mL
Remember, these are starting doses.
Please read below for maintenance dosages.
Epoetin Alfa (Epogen,
Eprex or Procrit): How to Measure
Because it is a human medication, epoetin needs to be divided into
cat-sized doses.
If you are giving epoetin at home (as many people do), you will need
to learn how to do this yourself.
Calculating how much to use can be very
confusing! Normally you will be told how many units to give, based on
your cat's weight. 1 cc of the 3000iu/mL strength contains 3000 units
of medication; 1 cc of the 2000iu/mL strength contains 2000 units; and
so on. We used the 1000iu strength of Eprex, which (just to confuse matters) is
slightly different: it contains 1000iu but in 0.5mL so it is the same
strength as the 2000iu/mL although it sounds different. Whichever you
use is less important than giving the correct amount.
It's best to let your vet measure the dose the first time and show you
how to do it. They can also show you how to inject it. However, here
is a quick guide in case you forget.
As you can see, the dosages are
pretty precise, but your vet will probably want to round the dose up
or down so as to make it easier for you to measure it.
USA
You will normally purchase the
2000iu/ml strength.
In other words, your vial contains one ml of liquid, which contains 2000
units of epoetin.
Let's take the example of a 10lb cat who is being given the standard
epoetin starting dose of
100 units per kg of cat. If you check the table above, you will see
that a 10lb cat weighs 4.5kg, so this cat needs 450 units (100 x 4.5)
of epoetin each time (normally three times a week to start with).
Your vial contains 2000 iu/ml, so it contains 4.4 doses altogether (2000
iu
divided by 450).
You have one ml of liquid in your vial, so you need to divide this by
4.4 (the number of doses it contains altogether), which results in
0.225 ml. Therefore you need to withdraw a little over 0.20ml ( a
little over 20% or one
fifth) of the medication each time you give it.
Instructions for use is an
instruction leaflet from Amgen, the manufacturer of Aranesp, which
explains how to draw Aranesp from the vial. The procedure is probably similar for Epogen, but
be guided by your vet.
You will
need syringes to draw and give the medication. Most people use human insulin
syringes. These are sold as U100 syringes, which means there are 100
units in 1 ml. They are usually available in three sizes, 1 ml (100
units), 0.5ml (50 units) or 0.3 ml (30 units), and most people use 0.5
or 0.3 ml syringes for cats (see
above for
sources). Unfortunately, insulin units are
not the same as Epogen units so working out the dose can be confusing.
As a general guide, one insulin unit is 0.01ml; so
each unit on an insulin syringe is 0.01ml; but the safest thing is to
ask your vet to measure out the doses for you and show you how much
you need to give.
Although the leaflet mentions that Aranesp
should only be used once, because cats need tiny doses and ESAs are
expensive, most people re-use their ESA vial with no problems, as long as
they store it properly (see
below).
UK
You will normally purchase the 1000iu/0.5ml
strength
In other words, your syringe contains
0.5ml of liquid, which contains 1000 units of epoetin.
Let's take the example of a 10lb cat who is being given the standard
epoetin starting dose of
100 units per kg of cat. If you check the table above, you will see
that a 10lb cat weighs 4.5kg, so this cat needs 450 units (100 x 4.5)
of epoetin each time (normally three times a week to start with).
Your vial contains 1000 iu/0.5ml, so it contains 2.22 doses altogether
(1000 iu
divided by 450).
You have half a ml (0.5ml) of liquid in your vial, so you need to divide this by
2.2 (the number of doses it contains altogether), which results in
0.225 ml. Therefore you need to withdraw a 0.225ml, or a little under
half, of the 0.5ml of medication each time you give it.
When we used Eprex, we used the syringe and needle in which the Eprex came,
giving half the vial each time. However, I am told that these days the
1,000 iu/0.5ml strength Eprex comes with safety syringes, which only work once.
Therefore, if you want to re-use the vial, you have to transfer the
contents into a sterile container, which is not exactly easy. The usual
method seems to be to
transfer the contents to an empty sterile vial, and measure it from there
with a small insulin syringe. Unfortunately this often means you end up
losing some of the Eprex, but it still works out cheaper than only using a
vial once.
Instructions
for use is an instruction leaflet from Amgen, the
manufacturer of Aranesp, which explains how to draw Aranesp from a
vial. The procedure is probably similar for Eprex if you decant it
into a vial, but be guided by your vet. You
will need syringes to draw and give the medication. Most people use
human insulin syringes. These are sold as U100 syringes, which means
there are 100 units in 1 ml. They are usually available in three
sizes, 1 ml (100 units), 0.5ml (50 units) or 0.3 ml (30 units), and
most people use 0.5 or 0.3 ml syringes for cats (see
above for sources).
Unfortunately, insulin units are not the same as Epogen units so
working out the dose can be confusing. As a general guide, one insulin
unit is 0.01ml; so each unit on an insulin syringe is 0.01ml; but the
safest thing is to ask your vet to measure out the doses for you and
show you how much you need to give.
Please see the additional
usage guidelines below
which apply to all ESAs.
Epoetin Alfa (Epogen, Procrit or
Eprex) Maintenance Dosage
Many vets
reduce dosing frequency to twice a week initially, but may then reduce
to once a week or eventually to once every 10-14 days. You may also be
able to reduce the amount given to 50-75 units per kg bodyweight. If
the anaemia begins to recur at these lower levels or frequencies, you
will usually need to increase the amount and/or frequency of the
injections (though you should also check for other possible causes,
see below).
It is very important to check your cat's PCV once
each week and before you
give that day's dose, in case your
cat's PCV is rising faster than expected.
states "Once the target range is
attained, an average maintenance dose of 50 to 100 U/kg once or twice
weekly is adjusted based on PCV monitoring."
Epoetin Beta:
NeoRecormon
Hoffmann LaRoche make a form of recombinant
human erythropoietin
(rhEpo) called
NeoRecormon. This is epoetin beta, rather
than epoetin alfa (Epogen, Eprex or Procrit are all epoetin alfa). As far
as I know, NeoRecormon is not available in the USA, but it may be offered
to you if you are in Europe.
I am not aware of any research into the use of NeoRecormon in cats, but my
vet has used it quite often for CKD cats.
Epoetin Beta (NeoRecormon): Where to Buy UK
My vet's wholesaler (Dunlops) can get this for them quite quickly, so this
might be the quickest way to obtain it.
If your vet can't help, you would have to call around your local
pharmacies as outlined above for
epoetin alfa (Eprex) in
the UK. In 2015, one member of my
support group paid
Ł256 for five vials.
Dosage and Usage Guidelines for NeoRecormon
I have only heard from a few people using
NeoRecormon. Most people seem to be using it in similar fashion to epoetin
alfa, giving it three times a week, but they usually give around 50-100iu per kg of body
weight (usually 100iu per kg of bodyweight is used for epoetin alfa).
I did find one reference about using it,
Veterinary Pharmacology, which suggests
the above dose but which also recommends that PCV should increase by 1% a
day for the first month (!), which seems inappropriate to me - I would
recommend the more usual target increase of 2% a week would be a more suitable
goal.
Please see the additional usage guidelines
below which apply to
all ESAs.
Giving an ESA: Usage Guidelines
Here are the basic guidelines to help you use your chosen ESA
as safely and effectively as possible.
These treatments are administered by
way of subcutaneous injection, i.e injecting under the skin. Your vet
can teach you how to do this so you can give the ESA to your cat
yourself at home - most on Tanya's Support Group do this. I used to give Thomas his ESA shot after his sub-Q
fluids, a short distance away from the sub-Q shot. ESAs may sting, although Thomas did not react too badly.
I am sometimes asked if it is possible to add the ESA
to the sub-Q fluids so the cat only has to be injected once. This is
not recommended, because it may dilute these extremely important and
expensive medications.
You will need to draw the correct dose for your cat from the vial or
syringe before you inject it. See above for dosages for
darbepoetin
and epoetin,
and for tips on how to measure the dose for
darbepoetin
and for epoetin.
Even if you give the ESA at home, you will still have to visit the vet at
regular intervals (once a week initially), in order to monitor your
cat's PCV level and blood pressure; but once the cat is on a maintenance
dose, less frequent checks are required (every 4-6 weeks). See below
for more on
monitoring.
Building
Blocks
In order to maximise the chances of your chosen ESA working properly,
you need to add a couple of building blocks:
"Iron
deficiency is present in 25–38% of anemic people with CKD",
and
Iron status of cats with chronic kidney disease
(2015) Gest J, Langston C & Eatroff A Journal of Veterinary
Internal Medicine29 pp1488-1493 found "Total iron binding capacity in this
population of cats with chronic kidney disease was significantly lower
than in this population of healthy cats."
Even if your cat is not iron deficient,
an iron supplement is usually given to cats receiving ESAs. This is
because the cat's
body will try to produce a lot of red blood cells
when you start giving an ESA,
but it needs sufficient
iron
in order to complete
the process; so an
iron supplement
helps ensure that your cat has the iron it needs to enable the ESA to do its work.
You can read more about iron supplementation on the
Anaemia
page.
B Vitamins
It is also a wise idea to give any anaemic cat
B vitamins,
particularly vitamin B12, because a lack of vitamin B can actually
cause or contribute to non-regenerative anaemia.
Anaemia of renal disease: what is it, what to do and
what's new (2011) Chalhoub S, Langston C & Eatroff A
Journal of Feline Medicine & Surgery13(9) pp629-40
says "Several B vitamins are necessary for erythropoiesis,
including cobalamin (B12), folic acid (B9), niacin (B3) and pyridoxine
(B6). Deficiencies of these vitamins may exacerbate anemia and increase
erythropoietin resistance."
They go on to say "Although there is a paucity of data on whether CKD
patients commonly develop deficiencies of these vitamins, supplementation
of these water soluble vitamins is unlikely to cause harm, but they are
not effective as sole therapies for anemia."
I would give B vitamins myself, because
they will not harm but they certainly seem to help some
cats feel better.
Target PCV or HCT
Level
How high should the PCV or HCT be? This is a tricky question these
days, to which there is no simple answer.
Although all laboratories have different ranges for normal values, as
a rough guide a normal PCV in a healthy cat would be in the 29-45%
range. When I was giving Thomas an ESA back in 1999/2000, it was
usually recommended to aim for a PCV of 35-40%, so the cat was no
longer anaemic, but firmly
in the middle to high end of the normal range.
Over time the recommended target began to fall, and people were
advised not to go
above 35% because higher levels
increase the chances of thrombosis and
associated heart problems (though very few cats I heard about seemed to
have a problem with a PCV or HCT of 35%). This target may have
become popular because it tied
in with the general recommendations for humans using ESAs.
In June 2011 the FDA recommended that a goal for PCV or HCT
levels should no longer be set for human patients on ESAs (see
below). Instead, it
states that the lowest dose sufficient to "reduce the need" for blood
transfusions should be used.
Perhaps because of this, gradually the recommendations for target PCV
for cats on ESAs have reduced, mainly in order to reduce the risks
associated with ESAs:
University of California at Davis recommends a target
range of 28-33%.
So what should be your goal?
Let's consider the Animal Medical Center recommendation of a PCV of
25%. With some laboratories, this would actually mean that the cat was
still anaemic or barely out of anaemic range (the PCV range for some
laboratories starts at 24%, but at 29% for others). I believe this
would be the case at AMC itself - when my cat had blood tested there,
the lab range began at 29%, although it is possible that the range has
changed since then. If your cat remains in the anaemic range, s/he
might still be experiencing some of the effects of anaemia.
A low target like this also gives you little room for manoeuvre should your cat
suddenly become more anaemic (perhaps because of sudden blood loss or
infection). It is relatively easy to arrange a
blood
transfusion for a human
whose anaemia suddenly worsens, with blood banks easily accessible almost
everywhere, but it is a lot harder (though not
always impossible) for a cat.
You might
decide not to aim for an exact target, but to monitor your cat and alter
your ESA dosing once the PCV is approaching normal range, as long as the symptoms of anaemia
have gone. If your cat is still showing signs of anaemia, however, you
may wish to cautiously aim for a higher PCV or HCT level. Generally
speaking,
a range of around 25-30%, depending
upon your laboratory's reference levels (25% if your laboratory's
range starts at 24%, or 30% if your laboratory's range starts at 29%), might be reasonable, but
aiming for 30-35%, as I have seen many people do successfully, might
also be appropriate, at least if your laboratory's range begins at 29%.
It's not easy, is it? When we made the
decision to use an ESA for Thomas, we decided to make sure he was no
longer anaemic. Despite all the increased knowledge about the use of ESAs
in cats today, I think I personally would still have the same goal today,
in which case I would aim for an HCT of around 30. Discuss with your vet
what would be most appropriate for your cat, but whatever you do,
monitor blood pressure carefully.
Monitoring PCV Levels
Your vet should check PCV and blood pressure a
week after starting treatment, and continue to check these weekly
until target PCV is reached and maintained for 3-4 weeks. Regular checks
should then continue every two weeks until the level is stable.
Therapeutic implications of recent findings in
feline renal insufficiency - proceedings
(2009) Scherk M CVC in
Kansas City Proceedings states "It is
important to monitor PCV every 2 weeks for the first 60-90 days to
check for development of anti-epo antibodies", but don't forget, you
are also monitoring blood pressure, so you should visit the vet once a
week initially.
Anaemia of renal disease: what is it, what to do and
what's new (2011) Chalhoub S, Langston C & Eatroff A
Journal of Feline Medicine & Surgery13(9) pp629-40
recommends also
performing a reticulocyte count each week until target PCV is reached,
and thereafter doing this monthly, but mentions
that the reticulocyte count does not always increase in cats receiving
darbepoetin.
In
Anemia of chronic kidney disease
(2009)
CVC in San Diego Proceedings Dr CL Langston suggests that "Monthly
monitoring is usually sufficient once the PCV has been stabilized. A
complete blood count should be checked monthly to bimonthly for the
duration of therapy." It also recommends checking iron measurements
before starting an ESA and then every 1-2 months thereafter.
If you are due to check your cat's PCV
level, always do it before administering the
next dose of an ESA, because you only want a rise
of around 2% a week (if it rises faster, it may increase the risk of
hypertension and other problems). If it is rising faster than this, apart from in the
first week (see
below),
then speak to your vet about whether you should adjust your dosing
regimen.
Unfortunately checking PCV frequently can be a bit problematic with
anaemic cats.
Managing anemia in patients with chronic kidney
disease
(2011) Chalhoub S, Langston CE Veterinary MedicineMay 2011 states
"The frequent blood sampling of hospitalized patients, especially
small pets, can contribute to anemia."
Fortunately, if you only need to test PCV, it is not
necessary to draw a lot of blood - a
tiny drop taken from the ear may be sufficient. See
Anaemia
for more on testing blood, including home testing machines.
Speed and Nature
of Response
In
Anemia of chronic kidney disease
(2009)
CVC in San Diego Proceedings Dr CL Langston says "Hematocrit
generally starts to increase within 1 to 2 weeks of starting ESA
therapy. The desired PCV typically takes 4 to 12 weeks to achieve."
Of course, it does depend upon your starting point (the more
severe the anaemia, the longer it will take to reach target range) and
whether, for example, your cat has received a blood transfusion before
starting the ESA.
However, the typical cat will not need a full twelve weeks. In
Anaemia of renal disease: what is it, what to do and
what's new (2011) Chalhoub S, Langston C & Eatroff A
Journal of Feline Medicine & Surgery13(9) pp629-40 Dr
Langston says "On average,
the target packed cell volume (>25%) is reached within 3–4 weeks of
ESA therapy."
Speed of Response: Darbepoetin Alfa (Aranesp)
Generally speaking, you will see a slower response with darbepoetin
compared to epoetin alfa.
Evidence-based step-wise approach to managing
chronic kidney disease in dogs and cats
(2013) Polzin DJ Journal of Veterinary Emergency and
Critical Care23(2) pp 205–215
states "Typically an increase in PCV occurs within 2-3 weeks."
In one study,
The use of darbepoetin to stimulate
erythropoiesis in anemia of chronic kidney disease in cats: 25 cases
(2012) Chalhoub S, Langston C & Farrelly J Journal of
Veterinary Internal Medicine23(2) pp363-369,
the median time for the cats to reach
target PCV level was only three weeks, but this was the median and
some cats needed longer (5-6 weeks). However, it does appear that
darbepoetin may work faster than was previously thought for some cats,
and it is certainly safer from the antibody reaction perspective.
Speed of Response: Epoetin Alfa or Epoetin Beta
It usually takes around 1-2 weeks for these ESAs to
start showing an effect, with PCV or HCT usually rising around 2% a
week. When I say by 2%, I mean, for example, a rise from 15% to 17%,
not 2% of the original level (15% in this example).
Although these ESAs may start to show an effect more quickly, they may
take longer than darbepoetin to reach the PCV target.
Managing anemia in patients with chronic kidney
disease
(2011) Chalhoub S, Langston CE Veterinary MedicineMay 2011 states that
"a response is usually seen within three or four weeks."
By response, they mean reaching the target PCV
level of 25%.
In
Chronic kidney disease (CKD) in dogs and cats -
staging and management strategies (2015) A Presentation to the
Virginia Veterinary Medical Association 2015 Virginia Veterinary
Conference, Dr D Chew states "Depending upon the severity of anemia, it may
require 3-4 weeks for the PCV to enter the target range."
Nature of Response
You normally want an increase in PCV of around 2% a week, though 1-3%
is an acceptable range according to
Anaemia of renal disease: what is it, what to do and
what's new (2011) Chalhoub S, Langston C & Eatroff A
Journal of Feline Medicine & Surgery13(9) pp629-40.
When I say by 2%, I mean, for example, a
rise from 15% to 17%, not 2% of the original level (15% in this
example).
Whichever
ESA is used, some cats will show an abrupt increase in PCV in the first week of
use, perhaps as much as a 10% increase. This is more likely to happen
in cats with less
severe anaemia (and in fact some of
them perhaps are starting the medication a little prematurely, before
PCV or HCT is below 20%), and/or
in cats with less severe CKD (creatinine under 5 ml/dl US or 450
µmol/L international) whose kidneys may still be able to make a little
erythropoietin on their own.
One analogy used is that if a fire has not gone out
completely, it is easier to fire it up again than if it has virtually
gone out. An abrupt increase of this nature in the first week is
probably not cause for concern as long as your cat's blood pressure is
under control, but if PCV continues to rise faster than 4% in
two weeks, you should ask your vet about reducing the amount given,
because rises in excess of this level have been associated with an
increased risk of hypertension and stroke in human patients.
Very occasionally, it is possible to
stop giving ESAs completely. This might be the case, for example, with
a cat who has
acute kidney
injury
rather than CKD and whose anaemia improves
as the kidneys start functioning again.
The use of darbepoetin to stimulate
erythropoiesis in anemia of chronic kidney disease in cats: 25 cases
(2012) Chalhoub S, Langston C & Farrelly J Journal of
Veterinary Internal Medicine23(2) pp363-369 reports on a
cat with
acute
on chronic kidney disease who was able to manage without an ESA
once he was stable.
However, in a cat with CKD it is unlikely
that you will be able to stop the ESA completely, and stopping and
starting is not recommended (see
below).
If PCV Does Not Rise
If your cat's PCV level does not rise, or if it rises and then begins to
fall, do not panic. You need to address all possible causes before
assuming it is the antibody reaction causing the problem.
Managing anemia in patients with chronic kidney
disease
(2011) Chalhoub S, Langston CE Veterinary MedicineMay 2011 states "Failure
to reach the target PCV with ESA treatment can be caused by a number
of factors, such as iron deficiency, anemia of chronic inflammation,
concurrent illnesses, infections, hemorrhage from gastrointestinal
erosions or ulcers, bone marrow failure or fibrosis, and pure red cell
aplasia."
The link
has a helpful table (in a pop up window halfway down the page)
entitled "algorithm to troubleshoot
persistent anemia (below PCV range) while using darbepoetin"
which your vet can use as a checklist if PCV is not rising
as you would expect.
Here are some of the possible causes of the problem:
Dehydration
Some cats' PCV may not rise, and in fact may fall in the first
couple of weeks of use of an ESA. This is quite common if your cat is
dehydrated when you first begin the treatment.
As mentioned in
Hemoglobin and Hematocrit
(1990) Billett HH in Clinical methods: the history, physical
and laboratory examinations, Third Edition, Eds. Walker HK, Hall
WD & Hurst JW chapter 151, dehydration inflates the PCV
value, so if your cat is dehydrated when PCV is tested, the value
will appear higher than it actually is. For example, if your
cat has a PCV level of, say, 20%, but is dehydrated when the
test is run, the level may appear lower (say, 18%) once the
dehydration has been brought under control. The severity of the fall would
depend upon the level of dehydration at the first check.
It may be that your cat is not dehydrated but PCV has fallen or not risen.
I know when this happens, some vets immediately say it is the antibody
reaction. That is unlikely because the earliest I have ever heard of the
antibody reaction occurring was after five weeks (one case only). There
are many other possible reasons for the PCV not increasing, so you need to
look at these first.
Building Blocks
You need to ensure all the building blocks to enable the ESA to work are
in place, such as B vitamins.
A cat who appears not to be responding to the ESA often
needs more iron.
Anaemia of renal disease: what is it, what to do and
what's new (2011) Chalhoub S, Langston C & Eatroff A
Journal of Feline Medicine & Surgery13(9) pp629-40
states that "Lack of available iron for erythropoiesis is recognised as
the leading cause of treatment failure in humans on ESA therapy." If you
have not been supplementing iron, therefore, you should consider this
possibility before fearing the worst. See
above for dosage
guidelines. Even if you have been supplementing iron, a lack of iron may
still be a factor because cats in the study who were receiving both an ESA
and oral iron supplements still had decreased iron levels.
Dosage
You need to review the dosage because you may not have
measured it correctly, or your cat may actually need more ESA than you
have been giving. Some vets give too small a dose in the mistaken belief
that this may reduce the risk of the antibody reaction. Plus some cats
simply need more ESA than others - Thomas's PCV went up and down in the
first few weeks of treatment so we were very worried, but we simply gave
him more of the ESA rather than less, and his PCV then rose steadily. A
cat whose CKD is advancing may also need more ESA than s/he previously
needed.
Anaemia of renal disease: what is it, what to do and
what's new (2011) Chalhoub S, Langston C & Eatroff A
Journal of Feline Medicine & Surgery13(9) pp629-40
states "In some cases, the ESA dose may be too low for the patient
or be incorrectly administered. A higher ESA dose may partially overcome
ESA resistance, although doses higher than 500IU/kg a week for epoetin
or1.5–2.0μg/kg a week of darbepoetin are rarely used by the authors."
Viability of the ESA
You need to consider whether your ESA is still viable. Perhaps it
was not shipped to you chilled, or it was left out of the fridge
overnight. Perhaps you have had the vial open for a long time and it is no
longer potent. If for some reason you
are using the 10,000 iu/ml strength of epoetin alfa (which is not recommended in
cats), or if you are giving darbepoetin (Aranesp) only every 3-4 weeks, the drug may lose its potency before you get a chance to finish the
vial. This can lead you to incorrectly suspect that your cat is developing
the antibody reaction.
One thing that may not occur to you is the way your pharmacy stores your
ESA before you receive it. One member of Tanya's CKD Support Group who
went to collect her ESA happened to see that it was up on the rack with
all the standard medications - the person who had unpacked it hadn't known
it needed to be refrigerated.
Infection or Inflammation
In
Anemia of chronic kidney disease
(2009)
CVC in San Diego Proceedings Dr CL Langston says that over 75% of
human patients whose anaemia does not improve on an ESA have an infection
or inflammation. She states "In a retrospective study of cats, 25 per cent
of patients did not reach the target haematocrit and were suspected of
having infection or inflammation (unpublished data, Langston and Kittrell,
2006). Higher doses of rHuEPO do not overcome the resistance; control of
the infection or inflammatory state is necessary."
Review Other Medications
Make sure your cat's phosphorus levels are under control
if at all possible, because high
phosphorus levels may reduce your cat's response to ESAs.
If you are giving an
ACE
inhibitor or ARB such as benazepril (e.g. Fortekor), these might
be a factor.
Anaemia of renal disease: what is it, what to do and
what's new (2011) Chalhoub S, Langston C & Eatroff A
Journal of Feline Medicine & Surgery13(9) pp629-40
states "Angiotensin-converting enzyme (ACE) inhibitors or angiotensin
receptor blockers are suspected to decrease angiotensin II-induced
release of erythropoietin, as well as prevent pluripotent hemopoietic
stem cell recruitment."
Other Issues
Other possible causes for a failure to respond to ESAs include hidden
blood loss (e.g. from
gastrointestinal bleeding)
or cancer. Ensure your vet checks
for and treats all
other causes of anaemia.
Try not to panic. Use the
checklist in the above
link and keep going.
If you do all this,
you should with luck start to see
an improvement after 2-3 weeks. In the meantime, depending upon how
severe your cat's anaemia is, you may have to consider a
blood
transfusion to tide your cat over until the ESA begins to work.
In some cases, the ESA will not fully resolve the anaemia. In one study,
The use of darbepoetin to stimulate
erythropoiesis in anemia of chronic kidney disease in cats: 25 cases
(2012) Chalhoub S, Langston C & Farrelly J Journal of
Veterinary Internal Medicine23(2) pp363-369,
76% of cats did respond to the use of ESAs, but this meant 24% did not
respond. Of those who did respond, 20% failed to maintain their
response over time. Some of these cats were suspected of having
persistent gastrointestinal bleeding and one was thought to have
FIP.
If PCV Increases Too Far
This is uncommon but it can happen occasionally, especially if you
give a dose of ESA without checking your cat's PCV level first. This
actually happened to Thomas, when a vet who was unfamiliar with ESAs
gave him a shot when he went in for a blood pressure check without
checking his PCV level first, and without realising I was actually
giving the shots myself at home. Thomas's PCV went up to, wait for it,
55%!
I have also heard of a couple of cats whose PCV rose too high because
their vet recommended the wrong dose or the pharmacy accidentally
dispensed the wrong strength of ESA.
The main risk here is that the blood thickens - my vet said Thomas
had raspberry jam running through his veins - which can increase the
risk of stroke and seizures. In such cases you need to monitor blood
pressure carefully and may need to place the cat on IV fluids to thin
the blood.
2013 AAHA/AAFP fluid therapy guidelines for dogs and
cats (2013) Davis H, Jensen
T, Johnson A, Knowles P, Meyer R, Rucinsky R & Shafford H Journal of
the American Animal Hospital Association49(3) pp149-159 states
"Treatment of symptomatic polycythemia involves reducing the
number of red blood cells through phlebotomy and replacing the volume
removed with balanced electrolyte solutions to reduce viscosity and
improve blood flow and O2 delivery."
And of course, definitely do not give any more ESA until
the level is down to a safe level. Fortunately Thomas was OK without
the need for IV fluids, and had no problems while his PCV gradually
reduced to a safe level.
So in the starting phase, please be sure not to give darbepoetin without checking PCV levels first; do
not give epoetin alfa or epoetin beta more than three times without
checking PCV levels first; and double check the dosage prescribed by your vet and
the ESA strength dispensed by the pharmacy.
Storage
and Lifespan of
ESAs
These medications usually contain no preservatives,
so MUST be kept in the refrigerator inbetween treatments, but since
the vials should not be shaken, do not keep them in the fridge door. It
is fine to leave the vial out at room temperature for 20-30 minutes
before administering it so it is not too cold when you inject your
cat.
One pharmacy did check with the manufacturer, Amgen, and was told that
it may be safe if an ESA is at room temperature for longer (possibly
up to a week) but only if the vial is sealed. Once the vial is open,
it must be refrigerated in under an hour.
You should not shake the vial, though
it is acceptable to roll it gently in your hand to warm it a little
before giving it to your cat.
Some pharmacists tell people they can
only use a vial once and then must throw it away; whilst this is true
for human patients, it is standard to re-use these products for cats. It is
unlikely that any problems will arise from doing so, as long as you
keep the vial or syringe sterile and do not use the medication
past its "use by" date.
Having said that, since maintenance doses
of darbepoetin (Aranesp) tend to only be given once every few weeks,
you may need to be more cautious if you are using an opened vial or
syringe. A
couple of my group members found that their cats' PCV began to fall
and they feared they were seeing the
antibody reaction;
however, when they switched to a new vial of darbepoetin, their cats'
PCV began to climb again. I would not keep an opened vial or syringe for longer
than 2-3 months. If you can afford it, it might be wise to ditch it
after around six weeks. Talk to your vet about the best approach.
ESAs: Side Effects and Interactions
The antibody reaction is discussed
below, but
that is not normally seen (if it occurs at all) until the cat has been
on an ESA for 4-5 months. This section focuses on the risks
to be aware of as soon as you start using an ESA.
Most CKD cats do not seem to have
problems when using ESAs, but possible side effects include vomiting,
fever, hair loss,
diarrhoea and occasionally seizures.
The use of darbepoetin to stimulate
erythropoiesis in anemia of chronic kidney disease in cats: 25 cases
(2012) Chalhoub S, Langston C & Farrelly J Journal of
Veterinary Internal Medicine23(2) pp363-369
discusses the use of darbepoetin and possible side effects. In this
study, four cats had seizures, but three of them also had
hypertension, which itself can cause seizures.
In fact
hypertension
is really the major concern when using an ESA, because in the worst case
hypertension may cause heart
problems or a stroke.
The use of erythropoietin(2003) Langston CE, Reine NJ & Kittrell D
Veterinary Clinics of North America Small Animal Practice33(6) pp1245-1260 found that 40-50% of cats on ESAs develop hypertension, so
blood pressure should always be monitored while
your cat is on an ESA, particularly when you first begin treatment.
Since CKD cats are prone to
hypertension anyway, ideally you should have started monitoring blood pressure as
soon as your cat was diagnosed with CKD; but if you have not been
doing this, do try to ensure that blood pressure is monitored once you
begin the ESA. If your cat's blood
pressure rises to an unacceptable level (see
hypertension
for information on target blood pressure levels) and your cat is not
yet on blood pressure medication, you will probably need to start it. If you are already
giving blood pressure medication, you may need to increase the dose.
You may also need to decrease the amount and/or frequency of the ESA,
at least until blood pressure is under control. Be guided by your vet
as to the best course of action in your cat's case.
See
above for the side
effects and interactions section.
The main
concern with the use of ESAs in cats is that in a small number of cases
(around 10% if you are using darbepoetin, around 30% if you are using
epoetin), an antibody reaction may occur.
In the worst case this will develop into pure red cell aplasia (PRCA).
ESAs are effective medications for most cats, but
there is one potential major disadvantage to using them.
Epoetin alfa and epoetin beta are recombinant human erythropoietins or rhEpo. Darbepoetin alfa is
slightly different (it is manufactured using recombinant human DNA
erythropoiesis stimulating protein).
With any of these medications (though it is less likely to happen with darbepoetin alfa), some cats
will eventually produce an antibody reaction because their
bodies consider the ESA to be a foreign body. These antibodies then neutralise
the ESA (i.e. stop it working to produce red blood cells), so the anaemia
returns. In this site I refer to this as the antibody reaction, but
elsewhere you may see this referred to as
PRCA, which is the most extreme
form of the antibody reaction.
Because of the risk of the antibody reaction, it is usually recommended
that cats should not be placed on ESAs until the benefits of using them outweigh the risks
(see above).
It is not known for certain how many cats go on to
develop this antibody reaction because it is hard to test for it. Some sites refer to a rate of around 70%
because of the only published clinical trial to date on the use of an ESA in cats,
Use of recombinant human erythropoietin for
management of anaemia in dogs and cats with renal failure (1998) Cowgill LD, James KM, Levy JK,
Egrie JC, Browne JK, Miller A & Lobinger R Journal of the American Veterinary
Medical Association212 pp521-8, in which the antibody reaction was seen in 5 out
of 7 cats treated with Epogen for more than six months. The dosing
schedule used was very different to that described below, and in other
research by some of the same researchers, the rate was found to be lower.
One of the researchers has advised me that in her experience, the rate for
the antibody reaction tends to be around 30%. In
Anemia of chronic kidney disease
(2009)
CVC in San Diego Proceedings Dr CL Langston
says that the rate seen at the Animal Medical Center in NYC is around 21%
for Epogen.
It
appears that darbepoetin alfa (Aranesp) may be less likely
to cause the antibody reaction. There has been one suspected case of the
antibody reaction in a dog at UCMVC but this was never confirmed. As at
September 2018I
have only heard of one apparently confirmed case in a cat. In
Anemia of chronic kidney disease
(2009)
CVC in San Diego Proceedings Dr CL Langston says that the rate seen at the Animal Medical Center in NYC is
around 10% for darbepoetin (this figure includes two
confirmed cases in dogs).
The use of darbepoetin to stimulate
erythropoiesis in anemia of chronic kidney disease in cats: 25 cases
(2012) Chalhoub S, Langston C & Farrelly J Journal of
Veterinary Internal Medicine23(2) pp363-369
states
"Of
the 11 nonresponders, PRCA was not clinically suspected in 9 cats because
other conditions were present that adequately explained the poor response.
PRCA was considered possible but unlikely in 2 cats. Neither cat was
documented to have reached the target PCV, but insufficient information
was available to determine if other conditions were present."
In my experience over the last eighteen
years of monitoring a number of CKD-related online groups, the frequency
of the antibody reaction in practice appears to be far lower than 25-30%
even when using epoetin alfa,
perhaps closer to 5-10%. See
below for a possible explanation of this discrepancy.
It is impossible to predict which cats will develop the antibody reaction,
although epoetin alfa in the form of Eprex appears to carry a higher risk of the antibody reaction for
humans than either epoetin alfa in the form of Epogen or Procrit, particularly if the HSA-free form of
Eprex (which contains polysorbate 80 instead of albumin, in order to
comply with European requirements) is used.
Erythropoietin-associated PRCA: still an unsolved
mystery
(2006) Schellekens H & Jiskoot W Journal of
Immunotoxicology3(3) pp123-130 has more information about this.
The antibody reaction does not usually occur in the first
month of use, and if it is going to occur it tends to be around 4-5 months after commencing treatment (only rarely does it happen
much earlier or later than this). There is no definitive test to show that
the cat has developed the antibody reaction; a bone marrow aspiration
(biopsy)
would provide some information in the form of a very high
myeloid to erythroid ratio (M:E ratio),
but this does not happen in every case. Bone marrow aspiration
is invasive and unlikely to be worthwhile for most cats.
Pet Place explains more about bone marrow
and bone marrow biopsy.
Skills laboratory: how to collect diagnostic bone
marrow samples (2005) Young KM &
Friedrichs KR Veterinary Medicine
has some information on
how this procedure is performed.
Diagnostic bone marrow sampling in cats. Currently
accepted best practices
(2017) Byers CG Journal of Feline Medicine & Surgery19(7)
pp759-767 is a more recent article on this subject.
From a practical perspective, the main sign of an antibody reaction
is that the cat's PCV value will steadily drop by approximately 2% a week,
despite the use of adequate amounts of an ESA. Large drops in PCV in the
space of a few days or a week are unlikely to be caused by the antibody
reaction, and other
possible causes
such as
gastrointestinal bleeding should be investigated. Rapid falls may
occasionally be
a sign of
PRCA, but this is
rare.
Please also read above
about possible causes for PCV not increasing - many of these may also be
factors in PCV actually falling too.
What Happens During the
Antibody Reaction
Whilst nobody wants their cat to experience the
antibody reaction, it must be stressed that it is not as awful as it
sounds. Some people think it is akin to anaphylactic shock but it is
nothing like that at all!
What normally happens is that the PCV gradually falls at
a rate of around 2% a week (any larger fall and you should search for another
cause, such as
gastrointestinal bleeding), despite the cat
being on an ESA. If the cat
is still producing a little erythropoietin naturally, the antibodies may
also neutralise the cat's own erythropoietin as well, at least for a
while, and this further worsens the anemia. In the worst case, a
condition called
PRCA can occur.
But, and most importantly, even in those
cats who develop the antibody reaction, the erythropoietin antibodies will
not always neutralise the effects of the ESA. In other words, some cats
may have the antibody reaction but you would never know it because the ESA
continues to work and the cat does not become anaemic again. This may
explain why it is often claimed that the majority of cats receiving epoetin alfa develop the antibody
reaction, yet in practice on the online support groups, the percentage
appears to be much lower, around 5-10%.
If your cat
does develop the antibody reaction to an ESA, since
the resulting anaemia will eventually kill the cat, the only remedy is to
stop using the ESA. It takes the cat's body 3-4 months until the
antibodies wear off, and during that period it is often necessary to keep
the anaemia under control via
blood
transfusions. You cannot start using the ESA
again, even after the antibodies wear off, so depending upon the level at
which your cat's anaemia stabilises, you may need to use blood
transfusions indefinitely. Some vet schools have been investigating using
darbepoetin in cats who have
developed an antibody reaction to epoetin alfa, you can read more about
this
In most cases the cat was suffering from severe anaemia,
otherwise an ESA would not have been started in the first place. So in the
worst case, using an ESA will have bought you an extra few months with
your cat; and in the best case, using an ESA could control your cat's
anaemia indefinitely.
Pure Red Cell Aplasia (PRCA)
In the worst case, the antibodies to an ESA which some cats develop may cause the cat
not only to neutralise his or her own erythropoietin but also to
develop a condition called pure red cell aplasia (PRCA), which
also kills off existing red blood cells. In such a case, the cat develops a sudden
loss of response to the ESA, the PCV level falls suddenly, and the reticulocyte
count will be extremely low. The cat will often be very lethargic and
short of breath.
Many vets believe that the antibody reaction to ESAs is identical to PRCA.
They therefore fear that the chance of this happening is as high as 70%,
and consider that any cat who suddenly becomes more anaemic despite being
on an ESA must be developing PRCA.
I see it more
as a question of degree. Whereas
some cats develop the antibody reaction mildly (so the ESA keeps on
working for them, see
above), those cats who develop
PRCA are exhibiting a reaction at the opposite end of the spectrum, which
also affects their existing red blood cells. In
Pure red cell aplasia clinical presentation
(2009), Dr Paul Schick states that "The development of pure red cell aplasia may represent the extreme end of the spectrum of EPO-induced
immunological suppression of RBC production."
PRCA is
thought to be an
autoimmune condition, and developing it as a result of using an ESA is rare - humans
on ESAs have a rate of PRCA of less than 1%. Most cases in humans on ESAs
occurred in people using Eprex prior to 2003, and cases tended to be
concentrated within certain countries such as the UK and France, whereas
Germany had hardly any. The cases that were seen coincided with a change
to the formulation of Eprex. The
currently available HSA-free form of Eprex, which contains polysorbate 80 instead of albumin
in order to comply with European regulations, had a higher PRCA rate; and
it was also thought that the way the drug was administered may have been a
factor (subcutaneous administration appeared to increase the risk).
Erythropoietin-associated PRCA: still an unsolved
mystery
(2006) Schellekens H, Jiskoot W Journal of
Immunotoxicology3(3) pp123-130 reports further on this issue.
Following prescribing changes in December 2002, even though the same type
of Eprex was being used, the number of human
cases of PRCA fell dramatically.
Epoetin-associated pure red cell aplasia: past,
present and future considerations
(2008) McKoy JM, Stonecash RE, Cournoyer D, Rossert J, Nissenson AR,
Raisch DW, Casadevall N & Bennett CL Transfusion48(8)
pp1754-62 explains more about the numbers involved.
PRCA appears to be more common in cats than in humans, though it is hard to know exactly
how many cats develop it because many vets do not differentiate between
PRCA and the less severe form of antibody reaction. It is also
fairly common for vets to assume a cat is developing PRCA when PCV falls
without addressing other posssible (and more likely) causes of the falling
PCV, such as infection or gastrointestinal bleeding.
PRCA
usually does not occur until the patient has been on an ESA for three
months. As far as cats are concerned,
The use of darbepoetin to stimulate
erythropoiesis in anemia of chronic kidney disease in cats: 25 cases
(2012) Chalhoub S, Langston C & Farrelly J Journal of
Veterinary Internal Medicine23(2) pp363-369
states "PRCA, one of the most serious complications of epoetin, has been reported
to occur after 5–38 weeks of treatment, with a
median of 14.5 weeks." In theory therefore, you
should be safe for the first few weeks of using epoetin alfa (Dr Katherine
James, one of the researchers into the use of epoetin alfa in CKD cats,
has stated that many cats do not have problems for 4-5 months); and don't
forget, even in the worst case scenario, your cat has a 70% chance of
never having this problem. If you are using darbepoetin (Aranesp), your
chances of being safe are really very high - your cat has a 90% chance of
never developing problems.
If your cat's PCV or HCT suddenly falls, whether during or after the first
three months of use, consider other causes before fearing the worst. You
can read above
about possible causes for PCV not increasing - many of these may also be
factors in PCV actually falling.
If, however,
your cat really does develop the antibody reaction so severely that PRCA
results, you must immediately stop using
the ESA. You might need to arrange a
blood
transfusion
for your cat. It takes the cat's body 8-10 months until the
antibodies wear off, and during that period it is often necessary to keep
the anaemia under control via regular blood transfusions. You cannot start using the ESA again, so depending upon the level at which your cat's
anaemia stabilises, you may need to use blood transfusions indefinitely.
Although this is a big commitment and expense, I do know of people who
have
done this successfully. Some vet schools have been investigating using
darbepoetin in cats who have
developed an antibody reaction to epoetin alfa, you can read more about
this
Please don't
feel guilty if your cat develops PRCA. Your
cat was most probably suffering from severe anaemia, otherwise an ESA
would not have been started in the first place. So in the worst case,
using an ESA will have bought you an extra few months with your cat; and
in the best case, using an ESA could control your cat's anaemia
indefinitely.
The cat of one of my support group members did experience PRCA following
the use of epoetin (Epogen), which was confirmed as far as it can be via a bone marrow aspiration and
by ruling
out possible other causes. The PCV began falling after six weeks of
treatment, eventually plummeting over a 24 hour period. Her vet began a
treatment protocol which involved stopping the Epogen for a few weeks,
giving the cat prednisolone (a corticosteroid) along with regular blood
transfusions, and later switching her to darbepoetin (Aranesp).
Unfortunately her cat developed antibodies to the blood transfusions, but
this method did buy her a few more months, and my group member did not
regret trying an ESA, but she wished she had started with
darbepoetin (Aranesp).
FDA Warnings
As mentioned above, there can be
other risks using ESAs,
such as high blood pressure, seizures,
heart problems and strokes (although controlling blood pressure does help
reduce the risk of many of these issues).
Various warnings relating to these concerns
have been issued by the US Food & Drug Administration over the years regarding the use of ESAs in humans.
The 2007 FDA warning
recommended aiming
for lower target haemoglobin levels than many doctors originally aimed
for, because this reduced the risks of serious side effects. Previously
many doctors aimed for a haemoglobin (Hb) level over 12, but the 2007 warning
recommended aiming for an Hb level of between 10 and 12.
Targets for human ESA patients are measured
in haemoglobin, but in haematocrit (HCT) or
packed cell volume (PCV) for cats. To convert Hb into HCT, you multiply by
approximately three. If the advice for humans was extrapolated to cats, this would
have meant that your target HCT (based on the maximum Hb level of 12) should be no higher than 36. Since it had long been recommended that people aim for a conservative HCT or PCV
level of no more than 35% in cats using these products, this
warning did not raise any additional concerns when it was issued.
The 2011 FDA warning,
issued in June 2011, states that humans on ESAs are
considered to be at greater risk of adverse events if they target an Hb
level of 11. The FDA now suggests considering starting an ESA when Hb
level falls below 10, but declines to state exactly when humans should start ESAs or
what level of Hb they should aim for. Instead it recommends individualised
dosing and states that the lowest dose sufficient to reduce the
need for blood transfusions should be used.
I discuss the implications of these warnings for cats
above.
Why Stopping and Starting ESAs is a Bad Idea
Very occasionally, it is possible to
stop giving ESAs completely. In fact, if your cat has
acute kidney
injury rather than CKD, you may
not need to start them in the first place - although cats with AKI tend to have high bloodwork
results generally, they often are not anaemic, or, if they are, the
anaemia resolves itself naturally as the kidneys begin working again.
However, I have heard that some vets
have a policy for every CKD cat they treat of using an ESA short-term
until the anaemia is resolved, then stopping it and starting it again
later when the cat has become anaemic again, in the mistaken belief
that this may reduce the risk of the antibody reaction.
This is really not a good idea. Dr
Katherine James, who participated in the Epogen trial in cats
mentioned
above (the
trial that has many vets worried about the antibody reaction in the
first place) has stated that there is no evidence either way, but she
suspects that doing this might actually increase the risk of the
antibody reaction occurring. She also believes that the resulting
fluctuations in PCV could cause problems with blood pressure control.
On the most basic level, I really do not
see the point of allowing a cat to become anaemic again, with all the
strains on the body and effects on the cat's quality of life which
that entails. Most scarily, I have heard from two people whose vets
insisted on this approach and their cats died of anaemia during one of
their anaemic phases. If you decide to use an ESA, I'd recommend
making a commitment to using it fully in order to keep your cat free
of anaemia, and in most cases this will mean using the ESA for life,
though of course as a maintenance dose.
Using
Darbepoetin in Cats Who Have Developed the Antibody Reaction to Epoetin
It is not recommended to use any form of
ESA in a patient who has reacted to another form (in other words, if you
have developed the antibody reaction to epoetin alfa in the form of Epogen, it is not advisable to use
darbepoetin alfa in the form of Aranesp instead). Since there are some
differences between epoetin alfa and
darbepoetin alfa, some US vet schools have tried to maintain cats who have
developed the antibody reaction to epoetin alfa by using blood
transfusions for several (6-8) weeks, and then starting them on
darbepoetin,
in the hope that the cats will not also develop an antibody reaction to
darbepoetin. Apparently there is anecdotal evidence that this approach worked
for one cat but it did not work for any others. Sometimes prednisone, a
corticosteroid, is
used in the interim period before starting treatment with darbepoetin.
One person whose cat may have developed the
antibody reaction to epoetin alfa (this person's vet had recommended a
stop/start approach,
which is not advisable because it may increase the risk of the antibody
reaction) tried to switch to darbepoetin. He found that using darbepoetin alone or
darbepoetin and prednisone did not help his cat, but using it in conjunction
with both
prednisone and chlorambucil (Leukeran), an immunosuppressive drug
commonly used in the treatment of cancer, did help for a while. This
regimen was based on the successful treatment plan for a woman who also
developed the antibody reaction. However, chlorambucil can itself cause
anaemia.
Feline non-regenerative immune-mediated anaemia:
features and outcome in 15 cases
(2016) Black V, Adamantos S, Barfield D & Tasker S Journal of Feline
Medicine & Surgery18(8) pp597-602 surveys the
treatment of anaemic cats including cats with
PRCA. Of the seven PRCA cats in the study, two died. Of the five surviving cats, most required blood
transfusions initially. Two of the cats with PRCA were treated with
prednisone and three were treated with prednisone and chlorambucil. All
five of these cats went into remisson after a maximum of six weeks and all
of them were still alive at follow up. The cause of the PRCA in the cats
in this study is not stated, but most of these cats were young so it was
probably not related to the use of ESAs.
Erythropoietin, cure or nightmare
(2004) Chan SK, Chan CK, Chow CC is a Presentation to the Hong
Kong Society of Nephrology Interhospital Meeting about a woman who
developed the antibody reaction and who was helped by prednisone and
chlorambucil.
Mar Vista Vet
has some information about
chlorambucil (Leukeran).
Should I Use an ESA?
I know it is not easy
making the decision to use an ESA, and your head is probably spinning
after reading this page (I've tried to make it as clear and simple as I
can, but I'm afraid it's a complicated subject). Please discuss the pros
and cons with your vet before making your decision. Remember, you should
not normally need to use an ESA if the cat's PCV or HCT is 20% or higher.
The criteria for knowing if it is time to consider using an ESA are
here.
If your cat does have severe CKD-related anaemia caused by a lack of
erythropoietin, then to some extent there is no real
decision to make, because the only real alternative to starting an ESA is
to watch your cat die of anaemia.
We decided to use an ESA for the following reasons:
It was quite obvious that if we did not do
so, the anaemia would kill Thomas long before the CKD would (he was
extremely weak, had no appetite and was breathless).
We felt the odds were in our favour with at least a
two to one chance that it would work for us. We used epoetin alfa;
the odds are much better with darbepoetin.
Even if he were to develop the antibody
reaction, it should buy him up to 4-5 months of additional time and thus
postpone having to say goodbye.
In the best possible scenario, once the ESA had done its work, we would
never have to worry about CKD-related anaemia caused by a lack of
erythropoietin again.
states "Treated animals demonstrate resolution of
anemia, weight gain, improved appetite, improved haircoat, increased
alertness, and increased activity."
Scherk M CVC in
Kansas City Proceedings
states "While there
is a risk of Ab developing, the majority of cats will enjoy the
benefits of an improved hemogram."
If your cat has HCM, a form of heart disease, I would give serious
consideration to using an ESA.
Hypertension, left ventricular hypertrophy and
chronic kidney disease (2011) Taddei S, Nami R, Bruno RM,
Quatrini I & Nuti R Heart Failure Reviews16(6) pp615-20
says of human patients "Left ventricular hypertrophy (LVH) is a
cardiovascular complication highly prevalent in patients with chronic
kidney disease (CKD) and end-stage renal disease... In particular, the
correction of anemia with erythropoietin in CKD patients is advantageous,
since it determines LVH reduction."
If you are considering the use of an ESA, don't take too
long to make your decision, because if you do, your cat may die of the
anaemia before the ESA has a chance to take effect (it may take up to
three weeks to see an improvement after starting to use an ESA, and the
anaemia should only improve gradually). If your cat has a low PCV level but is acting relatively well, don't be lulled into a false sense of
security. Because non-regenerative anaemia caused by CKD tends to develop
and worsen gradually, many cats' bodies do adapt to the anaemia so they
may not seem desperately ill, but they could still suddenly hit crisis
point. If necessary, a
blood transfusion
might help your cat through a critical period while
you wait for the ESA to take effect.
Personally I would never let PCV fall below
15% before starting an ESA, and if my cat was showing symptoms of anaemia
with a PCV of 16-19%, I would start it earlier. We began it as soon as
Thomas was diagnosed following his crash, when his PCV was 18% (though it
was probably lower, since he was severely dehydrated at the time -
as mentioned in
Hemoglobin and Hematocrit (1990)
Billett HH in Clinical methods: the history, physical and laboratory
examinations, Third Edition, Eds. Walker HK, Hall WD & Hurst JW
chapter 151,
dehydration makes PCV look higher than it really is. When
Thomas
died seven months later, his anaemia was completely under control. If we
had not used the ESA, he would have only managed a month at most.
So, to summarise:
I discuss research into possible new
anaemia treatments for CKD cats
here, but
at the present time (June 2016) there are no alternatives to ESAs
for the treatment of severe CKD-related non-regenerative anaemia. Milder
anaemia may be treated via the methods outlined
here.
if you do not use an ESA for severe CKD-related
non-regenerative anaemia, your cat will die of anaemia.
the antibody reaction is rare. Even going by the worst case statistics, your cat has less
than a 1 in 3 chance of developing the antibody reaction whilst on epoetin
alfa,
or only a 10% chance while on darbepoetin. That's a 90% chance in your favour! Based on what
I've seen over sixteen years of online support groups, your cat has more like
a 1 in 10 to 1 in 20 chance of developing the antibody reaction.
if your cat does develop the antibody
reaction, it will not usually be for 4-5 months, during which time your
cat will have no problems at all with anaemia.
if the antibody reaction occurs, your cat will normally become anaemic
again gradually, which simply means you will be back where you started 4-5 months
earlier when you first decided to use erythropoietin.
if the antibody reaction occurs, you will
see a fall in PCV/HCT of around 2% a week. A larger fall may indicate
PRCA, but may also indicate
some other cause, such as
gastrointestinal bleeding.
if your cat develops the antibody reaction, you will probably have to use
blood transfusions
to control the anaemia instead. At the present time I know of no other
treatment, except possibly switching to darbepoetin
if you are currently using another ESA.
if your cat, as is most likely, does not develop the antibody reaction,
s/he may well have no problems with anaemia and all its attendant side effects
in the future.
Ultimately it is your decision whether to use an ESA.
There have been trials into feline alternatives (see
below) but, according to
the researchers involved, none of these studies is
expected to result in the commercial availability of alternative
treatments in the foreseeable future.
If you do decide to use an ESA, darbepoetin
alfa (Aranesp) is usually the best choice.
What I Would Do
I know people find
this all overwhelming, and I am sometimes asked to make it simple. Well,
making the decision to use an ESA isn't simple, but once you've made the
decision and sourced your medication, it is less complicated. If I were
faced with anaemia in a CKD cat, I would
give darbepoetin
(Aranesp) using the 1mcg/kg per week dosage regimen.
begin using it
once my cat had a PCV below 20% with
non-regenerative anaemia caused by CKD and was showing symptoms of
anaemia. If my cat was not showing symptoms but PCV fell to 18%, I would
use darbepoetin regardless.
I would give my cat iron and B vitamins to
help the ESA work properly.
I would monitor my cat's blood pressure
Feline Erythropoietin (rfEpo)
I am only
covering these treatments briefly here because neither is commercially
available at the moment (2017), nor likely to be in the immediate future
unless you can participate in one of the current trials.
Feline erythropoietin was
developed in small quantities for use in two feline trials, one in 2010 at
Colorado State University and one in 2002 at Cornell.
It is not commercially available at present, but KindredBio has produced a
variant called
epoCat and field trials apparently began
in the third quarter of 2017.
CSU Feline
Erythropoietin Trial (2010)
The sponsor of this study at the Veterinary
Teaching Hospital at Colorado State University engineered a
new feline erythropoietin (rfEpo). In 2010 this was administered to
18 healthy cats at varying doses and on average, raised the red blood cell
count 25% or more with no side-effects and the effect lasted more than one
month.
Cornell Feline Erythropoietin Trial (2002)
A new synthetic form of feline
erythropoietin was developed at Cornell University in the USA, and a
one year trial for CKD cats was completed there in November 2002.
Expression,
bioactivity and clinical assessment of recombinant feline erythropoietin (2004) Randolph JF, Scarlett JM, Stokol T, Saunders
KM and McLeod JN American Journal of Veterinary Research65(10)
pp 1311-1450 explains the outcome of the study. Unfortunately, whilst the
rfEpo was effective at curing anaemia in the study cats, even in those
cats who had previously had an antibody reaction to human erythropoietin,
26% of the cats receiving feline erythropoietin (and who had never used
human erythropoietin) developed an antibody reaction to the feline
erythropoietin.
Feline Erythropoietin Gene Studies
2017 University of California at Davis
The Morris Animal Foundation is funding a
study assessing the safety and effectiveness of a new gene therapy
(presumably the one created during the 2011 research).
2011 University of California at Davis
The Winn Feline Foundation gave a grant in
2011 to the University of California at Davis College of Veterinary
Medicine to create a feline erythropoietin gene, with a view to using this
later in clinical trials.
Lentiviral gene therapy strategy for the in vitro
production of feline erythropoietin
(2012) Vapniarsky N, Lame M, McDonnel S & Murphy B PLoS
One7(9) e45099 discusses the outcome of the research.
2000 Ohio State University
A 2000 study at
Ohio State University College of Veterinary Medicine investigated the development of
a feline erythropoietin gene. The
gene that
makes feline erythropoietin was implanted into the leg or back muscle by an intramuscular injection similar to a vaccination.
Tests conducted on healthy cats showed that this increased PCV levels over
a seven week period following the injection.
Results were mixed with some cats responding extremely well and others
less well, but overall the trials were encouraging. Once the gene is
implanted, the cat should produce erythropoietin on its own, and in the
trials responsive cats had been doing so for up to one year. Further
trials may be conducted in due course.
Links on this page last
checked: 28 September 2016
*****
TREATING YOUR CAT WITHOUT VETERINARY ADVICE CAN BE
EXTREMELY DANGEROUS.
I have
tried very hard to ensure that the information provided in this website is
accurate, but I am NOT a vet, just an ordinary person who has lived
through CKD with three cats. This website is for educational purposes
only, and is not intended to be used to diagnose or treat any cat. Before
trying any of the treatments described herein, you MUST consult a
qualified veterinarian and obtain professional advice on the correct
regimen for your cat and his or her particular requirements; and you
should only use any treatments described here with the full knowledge and
approval of your vet. No responsibility can be accepted.
If your cat
appears to be in pain or distress, do not waste time on the internet,
contact your vet immediately.
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You may print
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Contact Me
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