• What are ACE inhibitors?

• Uses of ACE inhibitors

• Cautions, interactions and side effects

• Whether to use ACE inhibitors

Control of Intraglomerular Blood Pressure

As mentioned on the What Happens in CKD page, one of the kidneys' functions is to help to control blood pressure. There are two kinds of blood pressure in cats, within the cat's body generally (systemic blood pressure) and within the kidneys in particular (intraglomerular blood pressure).

It is not practicable to measure intraglomerular blood pressure in cats but it is usually higher than systemic blood pressure, and it may be elevated even if systemic blood pressure is not. If intraglomerular blood pressure is too high, it may cause loss of function and scarring in the kidneys.

ACE inhibitors work by preventing the conversion of a hormone called angiotensin I into another hormone called angiotensin II, the role of which is to constrict blood vessels. The ACE inhibitor relaxes the blood vessels, which helps to reduce both systemic and intraglomerular blood pressure (some blood pressure medications have no or only a limited effect on intraglomerular blood pressure).

This a delicate balancing act because reducing blood pressure within the kidneys can lead to a reduction in the amount of blood flowing through the kidneys, which in turn may reduce the glomerular filtration rate, a measure of kidney function. This may have a negative effect on kidney function in some cats, which may be seen in the form of elevated BUN and creatinine levels. One study, Effects of benazepril hydrochloride in cats with experimentally induced or spontaneously occurring chronic renal failure (2007) Watanabe T & Mishina M Journal of Veterinary Medical Science 69(10) pp1015-1023, found that benazepril appeared to improve creatinine levels as well as proteinuria in cats with naturally occurring CKD, but other studies have found the opposite.

How much of a problem this can be is debatable. ACVIM Consensus Statement: guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats (2007) Brown S, Atkins C, Bagley R, Carr A, Cowgill L, Davidson M, Egner B, Elliott J, Henik R, Labato M, Littman M, Polzin D, Ross L, Snyder P, and Stepien R Journal of Veterinary Internal Medicine 21 pp542–558 states that in cats who do not also have heart disease "the administration of ACEI commonly produces only very modest increases in serum creatinine concentration (0.5 mg/dL; 50mmol/L) and this degree of change is usually tolerable."

In most cats this increase is temporary, which should be tolerable in cats in the early stages of CKD. However, Novartis states that Fortekor can be used at any stage of the disease, i.e. as soon as there is any evidence of decreased renal function right through to cats with very elevated urea (BUN) and creatinine levels. In principle it is possible that a rise in creatinine levels in a cat in IRIS Stage 4 might be enough to push a cat over the CKD precipice. 

Control of Systemic Blood Pressure

Some vets also like to use ACE inhibitors to control systemic blood pressure. They may wish to do this simply because they think it is the best treatment, but they may also want to do so because of something known as the renin-angiotensin-aldosterone system or RAAS.

If blood flow to the kidney is reduced, the kidneys are stimulated to produce hormones called renin and angiotensin. The adrenal gland is stimulated to produce another hormone called aldosterone. This is known as the renin-angiotensin-aldosterone system (RAAS). These hormones make the blood vessels in the body constrict, which in turn leads to hypertension.

The RAAS can be activated by CKD, and may also be activated by the use of calcium channel blockers (such as amlodipine, the recommended treatment for hypertension in cats) to treat general hypertension. In contrast, since ACE inhibitors work by preventing the conversion of angiotensin I into angiotensin II, they not only do not activate the RAAS, they may reduce the risk of activation.

There is some debate as to how common activation of the RAAS is in CKD cats. In Feline hypertension: risks, diagnosis and management (2007) Atkins CE is a presentation to the World Small Animal Veterinary Association World Congress 2007 Dr Atkins states "several studies have indicated that the renin-angiotensin-aldosterone system (RAAS) is probably abnormally activated in many or, perhaps, most cats with systemic hypertension, particularly with concurrent renal disease." However, in Heart disease in the older cat (2006) Simpson K Presentation to the FAB Conference, Ms Simpson states that ACE inhibitors "appear fairly unreliable at decreasing blood pressure. A possible explanation for this may be that the hormonal axis which these drugs target (the reninangiotensin-aldosterone system (RAAS)) is not activated to the same degree in cats as in humans."

As Ms Simpson mentions, used alone, ACE inhibitors are not actually particularly effective at controlling systemic blood pressure. Effects of angiotensin-converting enzyme inhibition on plasma aldosterone concentration, plasma renin activitiy, and blood pressure in spontaneously hypertensive cats with chronic renal disease (2002) Steele JL, Henik RA & Stepien RL Veterinary Therapeutics: Research in Applied Veterinary Medicine. 3(2) pp157-66 found that "systolic blood pressure did not decrease below 170 mm Hg with ACE inhibitor monotherapy in 14 of 16 cats. These results suggest that continued activation of the RAAS is present in hypertensive cats despite treatment with an ACE inhibitor, and ACE inhibitors should not be used as first-line antihypertensive treatment in hypertensive cats."

Not only are ACE inhibitors not particularly effective at controlling blood pressure, they also cannot reverse the blindness sometimes caused by hypertension, whereas amlodipine may do so in some cases. Therefore, if your goal is to control systemic hypertension, particularly in acat who has gone blind, you normally start by using amlodipine only. ACVIM Consensus Statement: guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats (2007) Brown S, Atkins C, Bagley R, Carr A, Cowgill L, Davidson M, Egner B, Elliott J, Henik R, Labato M, Littman M, Polzin D, Ross L, Snyder P, and Stepien R Journal of Veterinary Internal Medicine 21 pp542–558 states that "In cats, although the renin-angiotensin-aldosterone axis may play a role in the genesis or maintenance of systemic hypertension, CCB [calcium channel blockers such as amlodipine] are often the first choice for antihypertensive therapy due to established efficacy." In Feline hypertension: risks, diagnosis and management (2007) Atkins CE A Presentation to the World Small Animal Veterinary Association World Congress Dr Atkins states that "the literature and clinical experience would, nevertheless, lead one to appropriately conclude that amlodipine is the single best agent for the management of feline systemic hypertension." See the Hypertension page for more information on using amlodipine.

One possible compromise is to use amlodipine and benazepril together, particularly for cats whose blood pressure cannot be controlled with amlodipine alone. Although ACE inhibitors are not massively effective at controlling blood pressure alone, they may provide a necessary boost without reducing blood pressure too far, whilst simultaneously reducing the risks of RAAS activation. Plumb's Veterinary Drug Handbook states "There is concern that using amlodipine alone for treating hypertension in cats with renal disease may expose glomeruli to higher pressures secondary to efferent arteriolar constriction. This is caused by localized increases in RAAS axis activity thereby allowing progressive damage to glomeruli. It is postulated that using an ACE inhibitor with amlodipine may help prevent this occurrence." The ACVIM Consensus Statement cited above also says "Combination therapy may be especially useful in cats, in which there  is some evidence for a beneficial effect of ACEI in CKD and for an established antihypertensive efficacy of CCB."

One area where benazepril appears to be effective is in reducing proteinuria (loss of protein in the urine, which may cause progression of CKD). It does this through its effects on GFR, which also minimises the risk of hypokalaemia (low potassium levels). In trials, cats with a urine protein:creatinine ratio greater than 1.0 who received benazepril showed improved appetite and weight gain, and had an average survival time of 402 days versus 126 days for those cats being treated with prescription diet only.

ACE inhibitors should be given two hours apart from phosphorus binders, because the binders may interfere with adsorbtion of the ACE inhibitors. Drugs has more information about this.

The potential downsides of using ACE inhibitors (a decreased GFR and increased creatinine levels) are usually considered to be an acceptable price to pay for the benefits (reduced intraglomerular pressure) in humans. This trade off appears to also be accepted for cats in Europe, Australasia and Canada, where benazepril in particular is routinely prescribed for CKD cats. In the USA, ACE inhibitors are not used routinely, and are usually only prescribed if a cat has significant proteinuria, or if amlodipine alone is not sufficient to control hypertension.

Prolonging life and kidney function (2009) Chew DJ & DiBartola SP Proceedings of the Southern European Veterinary Conference & Congreso Nacional states "Angiotensin-converting enzyme (ACE) inhibitors (e.g. enalapril, benazepril) may have protective effects in patients with chronic renal disease due to their ability to block adverse effects of angiotensin II. ACE-inhibition reduces glomerular capillary hydraulic pressure by decreasing postglomerular arteriolar resistance. Proteinuria is decreased secondary to decreased glomerular hydraulic forces and development of glomerulosclerosis is limited when protein trafficking across the glomerulus is decreased. Remnant nephrons in animals with CRF have glomerular hypertension that can benefit from reductions in transglomerular forces. An additional potential benefit from ACE-inhibition is improved control of systemic blood pressure. This beneficial effect must be balanced against their potential to worsen azotemia since glomerular pressure provides the driving force for GFR in the “super-nephron”.

Chronic kidney disease in dogs and cats II: Principles of management (2010) Maddison J & Syme H Irish Veterinary Journal 63(2) pp106-9 states" There is evidence that use of ACE inhibitors (such as benazapril) will attenuate the progression of renal failure in humans and animals with significant proteinuria. However, the evidence that they are beneficial in patients with mild proteinuria (the majority of cats) has not yet been clearly established. There is a rationale for using ACE inhibitors in cats and dogs with renal failure as there may be some benefit provided the patient can be pilled easily and the owner can afford the treatment. However, dietary change (reduction in phosphate) carries significantly greater potential benefits in slowing the progression of non-proteinuric renal failure and ACE inhibitor therapy should not be regarded as a substitute for it. Treating cats and dogs that are severely azotaemic, or that have pre-renal azotaemia with ACE-inhibitors may actually speed their demise."

The effects of Rheum officinale on the progression of feline chronic kidney disease (2011) Hanzlicek AS Thesis submitted to Kansas State University College of Veterinary Medicine states "Based on easily measured clinical parameters, this study failed to detect a significant difference in cats administered a Chinese rhubarb supplement, benazepril, or both."

Some members of Tanya's CRF Support Group have found benazepril helpful whilst others felt it did not suit their cat and in some cases caused problems. Personally, I would be prepared to use benazepril if I had a cat with proteinuria. I would also be prepared to use it if my cat had hypertension uncontrolled by amlodipine alone. I don't think I would use it in a cat without these problems, particularly not in a cat with creatinine over 3.5 (USA) or 310 (international). This level is arbitrary, and simply reflects my own feelings of what might be a reasonable cut off point.

If your vet offers you benazepril, please discuss it fully with him/her and try to decide together whether you think it could benefit your cat with his/her particular symptoms, bloodwork and quality of life.  If you do decide to use it, please check Side Effects and Interactions above, particularly the part about dehydrated cats. Whatever your cat's numbers, you should have bloodwork run 5-10 days after beginning to use benazepril, and monitor blood pressure.

Stem Cell Transplants                                                                                             Back to Page Index

As explained on the Research page, stem cell transplants have been shown to improve kidney function, prevent scarring and improve protein loss into the urine (proteinuria) in rats.

Mesenchymal stem cells help to produce bone, cartilage and cells that help with the creation of fibrous connective tissue. They have been used for some years to help dogs with arthritis, and US vet schools have been studying this type of stem cell with a view to helping cats with CKD. One study into the use of stem cell therapy for CKD cats has taken place at Colorado State University (see below), and another study is in progress at the Animal Medical Center in NYC.

Animal Medical Center, NYC

The Animal Medical Center is offering free stem cell treatment and three years long term management for qualifying cats. The cat needs to be in IRIS Stage 3 (i.e. creatinine level between 2.9 and 5.0) and must have a negative urine culture. The cat must have no history of stones or any other illness, although hypertension or proteinuria are acceptable.

The stem cells will be obtained and grown from the cat's own fat, and will be transplanted into the cat's renal artery via the femoral artery. This procedure will be repeated 2.5 weeks later. Follow up care will be available free of charge for three years. Only approved treatments and supplements may be used during this period.

Colorado State University

The Veterinary Teaching Hospital at Colorado State University has published the results of a preliminary study into stem cell transplants in cats with  stable chronic kidney disease (creatinine 2.0 to 5.0). Exclusion criteria included heart disease, kidney infection, stones in the ureter or other renal complications.

CSU found in earlier tests that it can be difficult to grow stem cells from older cats, which CKD cats often are, so they obtained and grew stem cells from the fat of young healthy cats (the cats were not harmed) and these cells were given to the CKD cat as an intravenous (IV) injection. The stem cell therapy was given once every two weeks for three treatments, and then monthly for three treatments if improvement was seen. At each visit bloodwork was performed and an IV catheter placed to administer the stem cell treatment.

A member of Tanya's CRF Support Group enrolled the first cat in this study in February 2009, and she told me that the initial cost (for tests and visits) was in the region of US$600, although she was given a lot of free prescription food. Her cat had stem cells injected into one kidney initially, and she said he was a little quiet immediately afterwards, which she thinks might have been caused by the mild anaesthesia he was given, but he seemed OK otherwise. After one month, it appeared his kidney function had improved by approximately 15% according to a scintigraphy scan which checks glomerular filtration rate (not every cat will undergo this, he did so because he was the first participant). His creatinine fell from 6 to 5.2 and his BUN from 80 to 66. Sadly, her cat had kidney stones before he took part in the study, and he died in June 2009, probably because of the complications caused by the kidney stones. Cats with kidney stones are no longer eligible for the study.

Evaluation of intrarenal mesenchymal stem cell injection for treatment of chronic renal disease in cats: a pilot study (2011) Quimby JM, Gibbons DS & Dow SW Journal of Feline Medicine & Surgery 13(6) pp418-26 reports on the study. It concludes "Despite the possible benefits of intrarenal MSC injections for CKD cats, the number of sedations and interventions required to implement this approach would likely preclude widespread clinical application. We concluded that MSC could be transferred safely by ultrasound-guided intrarenal injection in cats, but that alternative sources and routes of MSC therapy should be investigated."

Stem cell treatment is still available at Colorado State University for qualifying cats. See the Research Participation Opportunities page for more information.

Other Stem Cell Possibilities

There are three companies in the USA, Vet-Stem, Medivet and VivaStem, which offer stem cell treatments for vets to use on dogs with arthritis. Vets are trained by these companies to take stem cells from the dog, which they then send to Vet Stem, Medivet or VivaStem  for processing. The company then returns the cells to the vet for injection into the dog.

This treatment is not approved for CKD cats but Vet-Stem is apparently evaluating the use of its product for CKD in cats, though it is not running any trials. I am told Vet-Stem will permit this treatment to be given to CKD cats if your vet requests it. One member of Tanya's CRF Support Group was quoted US$3000 by her vet. She has subsequently had this done and her cat is recovering well, though he did not have it done because of CKD but because of severe immune-mediated anaemia.

Apparently there are a couple of vets in Australia who offer this treatment, and they seem to charge a lot less. I am told the injections are given every week for three weeks, by which time one would expect to see a difference in the cat in terms of improved appetite and reduced vomiting. I only know of one person to date whose CKD cat has had this treatment, she didn't think it helped.

Steroids                                                                                                                     Back to Page Index

Kidney Transplants                                                                                                Back to Page Index

• A Treatment, not a cure
• Ethical considerations

• Availability

A Treatment, Not a Cure

Some people are surprised to find kidney transplants listed as a treatment, but that is exactly what they are - a form of treatment, not a cure.

One centre has stated that the average survival time for a cat receiving a kidney at its facility is only 18 months; whilst The Animal Medical Center in New York has stated that 25% of cats who undergo transplants there do not even survive the initial operation of receiving the kidney, and only 60% survive one year. Even at one of the most longstanding centres, The University of California at Davis, 20-25% of cats died in the year following the transplant. Another vet school with extensive experience, University of Pennsylvania School of Veterinary Medicine, states that approximately 60-70% of recipients are still alive after one year.

Problems arise for a number of reasons. Firstly, this is major surgery, and by definition it is being performed on seriously sick cats. Secondly, immuno-suppressive drugs (usually cyclosporine), which stop the body rejecting the new kidney as a foreign body, are required. These must be given religiously at set times (usually every twelve hours), but even so, they may not work for every cat, and then the new kidney is rejected by the cat's body and ceases to work. Since these drugs suppress the immune system, transplant recipients are also vulnerable to infections, which may damage the new kidney.

Unfortunately these anti-rejection medications also increase the chances of the cat developing cancer, with a 14% incidence rate reported in cats at one facility who survived more than one year after the transplant. 10% of cats also develop diabetes.

Because of the foregoing, as The University of California at Davis has stated, "Due to all the inherent risks with transplantation, it is not considered a prophylactic procedure, and those cats that are doing well with medical management are not considered candidates for transplantation."

Transplants are also extremely expensive: the Animal Medical Centre in NYC estimated the cost at US$8000 for the initial surgery and hospitalisation, follow-up care at US$4000 in the first year and medications and check-ups at US$3000 for each further year. University of Pennsylvania School of Veterinary Medicine gives the cost of the initial transplant as US$12500.

Ethical Considerations

The transplanted kidney is taken from a healthy cat, who usually then goes to live with the family of the recipient. The major UK charities, Cats Protection, the RSPCA and the Feline Advisory Bureau, are opposed to kidney transplants because of the ethical issue of removing a kidney from a healthy donor cat with no benefit to that cat, a concern which I share. It is often argued that using a shelter cat "saves a life"; but in the UK, very few cats are euthanised compared to the millions in the USA; and in any event, all the US transplants I have heard about in recent years used a cat purpose-bred by the transplant facility, so no shelter cat was "saved". I also wonder what would happen should the donor cat develop CKD him/herself later in life; presumably such a cat, with only one functioning kidney, would develop end stage renal failure more quickly than a cat with two kidneys.

Both Cats Protection and the RSPCA have stated that they will not supply cats as donors, and Cats Protection have gone so far as to state that they would "support rigorous punishment measures for any individual who acquires a cat, through whatever means, to use as a donor for feline kidney transplantation".

Availability

Kidney transplants are available at a limited number of facilities in the USA and at one location in Australia. The Animal Medical Center in New York and The University of California at Davis are not currently performing kidney transplants.

Transplants have not yet been performed in the UK, but on 27 February 2003, the Royal College of Veterinary Surgeons (RCVS) issued guidelines for the procedure. According to the RCVS, the guidelines were published in order to ensure the highest welfare standards for both the recipient and the donor. The RCVS envisages that approved transplant centres will have to meet very strict criteria, so it is expected that it will be quite some time, perhaps even years, before it is possible to perform the procedure in the UK. They are not currently (January 2012) available in the UK.

I do find it ironic that the RCVS is prepared to permit kidney transplants when it makes so little effort to promote other, far cheaper and less invasive treatments such as sub-cutaneous fluids.