What are Erythropoiesis Stimulating Agents

The kidneys produce a hormone called erythropoietin which stimulates the bone marrow to make red blood cells. 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, but this is the most common reason for it in CKD cats.

Some vets seem to rush to use ESAs as soon as a cat is diagnosed with anaemia. Others seem to be terrified to use them because of the risk of an antibody reaction developing a few months after starting ESAs. Depending upon the severity, type and cause of the anaemia, there are other treatments which may be more appropriate and which are certainly cheaper. See the Anaemia page for more information.

The basic criteria for using ESAs are as follows:

• The PCV or HCT (a measurement of anaemia) will be between 15% and 19%, or even lower, and the cat will be showing signs of anaemia, such as breathlessness, lethargy or severe loss of appetite. Managing anemia in patients with chronic kidney disease (2011) Chalhoub S, Langston CE Veterinary Medicine May 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.

• The cat should have non-regenerative anaemia rather than regenerative anaemia. A reticulocyte test can confirm this, although this test is only accurate if the PCV or HCT has been below 20% for five days or longer.

• 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 a certain extent. Cats who develop sudden, severe anaemia should be checked for other causes, such as gastro-intestinal bleeding.

• Usually (but not always, particularly in older cats) the CKD will be relatively advanced, with creatinine over 5, 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.

Types of Erythropoiesis Stimulating Agents

There are two categories of ESA which have been used in CKD cats:

Human Erythropoietin (ESAs)

Since feline erythropoietin is not commercially available, most people whose cats need erythropoietin supplementation will have to use human erythropoietin. It takes the place of the cat's natural erythropoietin and enables the bone marrow to continue to make red blood cells. 

There are a number of different types of human erythropoietin, as outlined in the table below. Although these products all have the same goal, technically they are not exactly the same, so they are referred to collectively as erythropoiesis stimulating agents (ESAs).

These are all types of the epoetin alfa variant of recombinant human erythropoietin:

• Epogen, made and sold by Amgen, is the synthetic version of epoetin alfa used in the USA for the treatment of anaemia in human CKD patients on dialysis.

• Procrit is the same product, epoetin alfa, made by Amgen but 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.

• Eprex 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.

See below for the dosing protocol for Epogen, Procrit and Eprex and how to obtain it at a reasonable cost.

NeoRecormon (epoetin beta)

Amgen, the manufacturers of Epogen, also make another type of ESA called Aranesp (darbepoetin alfa). This is slightly different to the other ESAs (Epogen, Procrit, Eprex and NeoRecormon, all recombinant human erythropoietins or rhEpo), in that it is an erythropoiesis stimulating protein which 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.

See below for the dosing protocol for Aranesp and how to obtain it at a reasonable cost.

Which Erythropoiesis Stimulating Agent To Choose

The 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.

Epogen and Procrit (which is the same treatment with a different name) have been used in CKD cats in the USA for many years. It was the subject of a clinical trial in 1998, 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 Association 212 pp521-8), in which 30% of cats developed the antibody reaction.

Eprex has been used in CKD cats in the UK for many years - I myself used it for Thomas in 1999 with no problems. Janssen-Ortho, the manufacturer, mentions 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. Erythropoietin-associated PRCA: still an unsolved mystery (2006) Schellekens H, Jiskoot W Journal of Immunotoxicology 3(3) pp123-130 reports further on this issue.

I am not aware of any research into the use of NeoRecormon in cats, but my UK vet now uses it routinely for CKD cats. I think if I had an anaemic cat, I would probably favour it over Eprex these days.

Another factor to consider is which product your vet is comfortable using. Some vets have never used ESAs, in which case it will be a learning curve for both of you. But if your vet has a lot of experience using, say, Epogen, you might feel more comfortable using that.

Overall, Aranesp is probably the best choice, certainly from the antibody reaction perspective, and is the treatment of choice at major US vet schools. There are a few possible downsides to be aware of:

1. It costs a lot more than 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.

2. It may take longer to start taking effect. This can be a problem if your cat's anaemia is particularly severe and you want to start making a difference as quickly as you can.

3. It can be hard to work out the best dose for an individual cat. Some cats respond too well to Aranesp, which carries risks too.

I think overall Aranesp is the best choice and is what I would choose to use myself. However, if your cat has critically severe anaemia, or if 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.

Treatment with Erythropoiesis Stimulating Agents

Some vets think ESAs costs hundreds of dollars, and therefore may not bother to prescribe them. However, it is usually possible to obtain these products for just a few dollars (or pounds) a dose if you know where to look.

Aranesp (darbepoetin alfa) - USA

Aranesp is more expensive than Epogen. It is sold as a single use human medication but is routinely used in veterinary medicine for multiple doses. You need the 25mcg vial size which costs around US$150. This size vial contains approximately feline 4-10 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 Epogen, the cost should work out about the same overall. You will need a prescription from your vet.

Some of the pharmacies below offer family savings plans whereby you pay an annual membership fee and then receive a discount on the price of your prescription medications. These schemes often permit cats to be enrolled as family members, which may further reduce your costs. One member of my support group has printed out the free Pet Medication Card and has successfully used it to obtain discounts at some pharmacies. Pet Med Saver Card and the RX Free Card also offer discounts, but I don't know anybody who has used them as yet.

It is usually easier to obtain price quotations if you have the NDC reference numbers for the products you are interested in. The NDC reference number for a single vial of Aranesp is NDC 55513-002-01. For a pack of four vials of Aranesp it is NDC 55513-002-04.

Epogen or Procrit - USA

In the USA most people use the 2,000iu strength of Epogen. This is a single use human medication but is routinely used in veterinary medicine for multiple doses. You do not want the 10,000iu and higher strengths, because it is too hard to obtain cat-sized doses from these.

A 2,000iu strength vial will cost around US28-$36, and depending upon your cat's weight this would usually be enough for 5-8 doses.

Some of the pharmacies below offer family savings plans whereby you pay an annual membership fee and then receive a discount on the price of your prescription medications. These schemes often permit cats to be enrolled as family members, which may further reduce your costs. One member of my support group has printed out the free Pet Medication Card and has successfully used it to obtain discounts at some pharmacies. Pet Med Saver Card and the RX Free Card also offer discounts, but I don't know anybody who has used them as yet.

• Walmart Specialty Pharmacy sells Epogen for around US$30 per 2,000iu vial (a vial will provide several treatments). The website does not show prices so this is the approximate price but a member of Tanya's CRF Support Group was quoted US$30 in September 2011. Another member paid US$98.17 in July 2011 for three vials of Epogen, syringes, needles, a sharps container and overnight shipping. Note: this is Walmart Specialty Pharmacy, which deals with complex therapies such as ESAs. You must use the link 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. It can take a few days to complete the registration process the first time you order. Wal-Mart will contact you to ask for your preferred delivery date, so you can be sure you are there to receive it.

• Walgreens sells one vial of the 2,000iu strength for around US$39, or three vials for a little less per vial). The website does not currently show prices so this is the approximate price. Walgreens also sells six of the 2,000iu strength of Procrit (same drug as Epogen) for around US200.

• Family Meds sells ten vials of the 2,000iu strength of Epogen for US$233.87, which works out at US$23.39 a vial, but ten vials are a lot to buy at one time. Family Meds also sells six vials of the 2,000iu strength of Procrit (same drug as Epogen) for US$171.87, which works out at US$28.65 a vial.

• Drugstore sells Epogen for US$38.31 per 2,000iu vial but there is also a US$17 overnight delivery charge, so you might prefer to order several vials at one time.

If you don't want to order online, some local pharmacies in the USA, such as Walgreens, can order Epogen with overnight delivery for around US$30-35 per 2,000iu vial. Hospital pharmacies often have Epogen in stock and may well be prepared to sell it to you with a prescription.

Aranesp is more expensive than Epogen. It is sold as a single use human medication but is routinely used in veterinary medicine for multiple doses. You need the 25mcg vial size. This size vial contains approximately feline 4-10 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 Epogen, the cost should work out about the same overall. You will need a prescription from your vet.

Eprex - UK

This is a single use human medication but is routinely used in veterinary medicine for multiple doses. Eprex is available in various strengths but you do not want the 10,000iu and higher strengths, because it is too hard to obtain cat-sized doses from these.

You will usually be offered the 1,000iu strength, which confusingly is the same as the 2,000iu strength, but half the amount. Obviously, if you are using a lower strength, you need to give more of it. Your vet should be able to advise you on which strength to buy.

NeoRecormon - UK

If your vet can't help, you would have to call around your local pharmacies as outlined above for Eprex.

Aranesp- Canada

Aranesp is more expensive than Epogen. It is sold as a single use human medication but is routinely used in veterinary medicine for multiple doses. You need the 25mcg vial size. This size vial contains approximately feline 4-10 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 Epogen, the cost should work out about the same overall. You will need a prescription from your vet.

• Walmart in Canada sells Aranesp. In November 2008 one person was quoted CA$133 for four vials of the 25 mcg 0.4ml.

• Benefit RX sells Aranesp for US$145. I do not know anybody who has used them yet.

• You could also ask your vet for a price.

Eprex- Canada

This is a single use human medication but is routinely used in veterinary medicine for multiple doses. In Canada, Eprex is available in various strengths but you do not want the 10,000 iu and higher strengths, because it is too hard to obtain cat-sized doses from these.

When we used Eprex, we did not need insulin syringes; instead 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 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.

• Walmart in Canada sells six vials of 1000 iu strength Eprex for around CA$110.

• 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 strength Eprex from her local pharmacy for CAN$119.

• If you cannot find a Canadian supplier, Entirely Pets in the USA sells Epogen for US$45.99 for a vial of the 2000iu strength and will apparently ship to Canada.

Australia and New Zealand

Although both Eprex and Aranesp are approved for human use in these countries, unfortunately it can be hard to obtain human erythropoietin in practice. This dates back to the Sydney Olympics, when the use of ESAs was severely restricted in order to make it harder for athletes to abuse the medication.

Aranesp - Australia

Aranesp is supplied in Australia by Amgen Australia Pty Ltd Level 7, 123 Epping Road, North Ryde. NSW 2113 Tel (02) 9870 1333.

Eprex- Australia

Your best bet is probably a hospital pharmacy, with a prescription from your vet.

Here are the basic guidelines to help you use your chosen ESA as safely and effectively as possible.

How to Give ESAs

Use of erythropoietin and calcitriol for chronic renal failure in dogs and cats (2005) Sanderson S Presentation to the World Small Animal Veterinary Association World Congress 2005 explains more about when and how to supplement iron when using ESAs.

Speed and Nature of Response

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.

It is possible that the various vet schools may revise the higher targets for cats mentioned above in light of the FDA recommendations for human ESA patients; but with cats there are other factors to consider. Let's consider the Animal Medical Center recommendation of a PCV or HCT of 25%. With some laboratories, this would actually mean that the cat was still anaemic or barely out of anaemic range (the HCT range for some labs 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 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.

Therefore, in practice I think "reducing the need" for blood transfusions would not be the best choice for most cats, especially since there is a risk of an antibody reaction to repeated blood transfusions in cats. Avoiding the need for transfusions seems more appropriate, especially for those who do not live in a big city with prompt access to blood transfusions; and even those who do live in such a place might wish to avoid the costs and inconvenience and worry of a transfusion.

You might decide not to aim for an exact target, but to monitor your cat and alter your ESA dosing once the HCT or PCV is approaching normal range and at a stable level, 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 in the 30-35% range, but monitor blood pressure carefully. Discuss with your vet what would be most appropriate for your cat.

Frequency of Dosing

Once the PCV or HCT level is close to your goal, the dose frequency is reduced to whatever level is necessary to maintain the PCV or HCT at the desired level.

With Aranesp, it is usual to reduce the frequency from once a week to once every 2-3 weeks. Apparently many cats only need a maintenance dose every 3-4 weeks. 

With Epogen, Procrit, Eprex or NeoRecormon, 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 as low as 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, such as infection or gastro-intestinal bleeding).

There is a timelag of approximately 1-2 weeks between giving the ESA and seeing its effects on PCV or HCT, so you need to bear this in mind when adjusting dosages because PCV or HCT levels will continue rising for some time after each dose.

Once a cat has reached a stable PCV or HCT on an ESA, I would recommend still checking PCV or HCT every 4-6 weeks in order to ensure that your cat is not developing the antibody reaction, and I would also get blood pressure checked at the same time.

How to Check PCV or HCT

When testing PCV or HCT, it is not necessary to draw a lot of blood (which could worsen the anaemia) - a tiny drop taken from the ear may be sufficient. Veterinary Partner has a description of how this is done in diabetic cats, as does Sugar Cats.  Some machines do need more blood than this, but it's worth asking your vet if this method could be used because in most cases it can.

Several members of Tanya's CRF Support Group use a home hematocrit tester. It is expensive (in August 2011 one person paid US$150 for the machine but the total cost including accessories and shipping costs was US$195) but over time it can pay for itself, and it is certainly less stress than regular trips to the vet. If you wish to purchase one, try this ebay link - he will ship worldwide. If the link is broken (it changes regularly) the e-mail address at the bottom of this link is still valid, so make contact that way. If you do buy a home tester, I would recommend checking your first few readings against readings at the vet's, to make sure you are doing it properly and to reassure your vet that you are obtaining accurate readings at home. I'd also advise caution if you are dealing with severe anaemia (PCV below 18%), because because when PCV is so low, every percentage point matters, plus vet visits give your vet the opportunity to check blood pressure as well as checking PCV. If you do buy one of these machines, please check its readings against those from your vet's equipment..

One possible compromise would be what one member of Tanya's CRF Support Group used to do. He would obtain the blood from his cat's ear at home as outlined above, but then take the sample to his vet for analysis. This saved his cat the stress of the vet trip, but still gave an accurate result.

Risks and Side Effects of ESAs

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 hair loss, diarrhoea and very rarely seizures.

The major concern when using an ESA is hypertension, which in the worst case 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 Practice 33(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.

There is some debate as to whether ACE inhibitors may exacerbate anaemia and/or induce some resistance to the use of human erythropoietin in humans. The role of ACE inhibitors and angiotensin II receptor blockers in the response to epoetin (1999) MacDougall IC Nephrology Dialysis Transplantion 14 (8) pp1836-1841 reports on the evidence for and against this concern in humans. If your cat is on both an ESA and an ACE inhibitor such as Fortekor, I would discuss this with your vet.

Dosage Guidelines

• Commonly Used Dosages

• Calculating Your Cat's Dosage

• Commonly Used Dosages

Calculating Your Cat's Dosage of Aranesp

 

If Dosage of 0.45 mcg per KG in Weight is Prescribed
	8 lb (3.65kg) Cat	10 lb (4.5kg) Cat	12 lb (5.45kg) Cat
Aranesp Dosage	1.64mcg	2.03mcg	2.45mcg

If your cat's PCV rises too quickly (more than a 2% increase in PCV or HCT per week), ask your vet about reducing the dose or giving the Aranesp less frequently, because it is important to adapt the dosing schedule to what works for your cat.

Dosage and Usage Guidelines for Epogen, Procrit or Eprex

• Commonly Used Dosages

• Calculating Your Cat's Dosage

Plumb's Veterinary Drug Handbook (6th edition) (2008) by Donald C Plumb suggests using 100 units of Epogen, Procrit or Eprex per kg (2.2lbs) of bodyweight, given sub-cutaneously three times a week, until you begin to approach the target PCV level (usually around 35%). 

Some cats may require higher doses initially, particularly cats with severe anaemia. For cats whose PCV or HCT is below 14%, Plumb's suggests using up to 145 units per kg (2.2lbs) of bodyweight, also given sub-cutaneously three times a week. You may also wish to discuss this dosage level with your vet if your cat does not appear to respond to the treatment at the initial starting dose outlined above.

However, a lower dose of 48.4 units per kg (2.2lbs) of cat, sub-cutaneously three times a week, may be advisable if the cat has hypertension (high blood pressure) before starting Epogen, Procrit or Eprex, or if hypertension appears after starting.

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.

Calculating Your Cat's Dosage of Epogen, Procrit or Eprex

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 use the 2000iu/mL strength. If for some reason you do end up using the 10,000 strength and above, be aware that the medication 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.

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.

If you are using Epogen or Procrit, you will probably also need syringes to 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.

1. The cost: vets often mistakenly believe that it costs hundreds of dollars when in fact, depending upon your cat's size and the severity of the anaemia, it may cost as little as US$5-10 per dose (see Obtaining ESAs at Reasonable Prices).

2. They fear possible side effects as follows:

• The Antibody reaction

The Antibody Reaction

It is impossible to predict which cats will develop the antibody reaction, although Eprex appears to carry a higher risk of the antibody reaction for humans than either 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. There is more information about this from Janssen-Ortho, the manufacturers of Eprex. Erythropoietin-associated PRCA: still an unsolved mystery (2006) Schellekens H, Jiskoot W Journal of Immunotoxicology 3(3) pp123-130 reports further on this issue.

The antibody reaction does not usually occur in the first month of use, and if it is going to occur it almost always happens 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, but is invasive and unlikely to be worthwhile. Pet Place explains more about bone marrow and bone marrow biopsy. Washington State University College of Veterinary Medicine has some information on how this procedure is performed. 

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 gastro-intestinal bleeding should be investigated. Rapid falls may ocassionally be a sign of PRCA, but this is rare.

To complicate matters further, your cat may actually need more ESA than you have been giving: many vets give a too small 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. A cat who appears not to be responding to the ESA may also need more iron. If for some reason you are using the 10,000 strength and above (which is not recommended in cats), 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.

Other possible causes for a failure to respond to ESAs include a lack of folic acid (Vitamin B9) or Vitamin B12, infection, inflammation, cancer or  hidden blood loss (e.g from gastro-intestinal bleeding).

So if PCV levels do begin to fall, you should not automatically fear the worst, but instead should consider all other possible causes of the fall. In Anemia of chronic kidney disease (2009) Langston CL 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 hematocrit 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."

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 gastro-intestinal 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.

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. 

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 renal failure rather than CKD, you may not need to start them in the first place - although cats with ARF 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.

Many vets believe that the antibody reaction to ESAs is identical to PRCA. They therefore fear that the chance of this happening is around 30%, and consider that any cat who suddenly becomes more anaemic despite being on an ESA must be developing PRCA.

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 Aranesp in cats who have developed an antibody reaction to Epogen or Eprex, you can read more about this here.