Proteinuria means there is excess protein in the urine.
It is important to know if it is present because it may make
CKD progress faster.
It is also used to help determine the stage of CKD.
This page explains more about proteinuria and
how you can deal with it.
What is
Proteinuria?
Healthy cats only have tiny
amounts of protein in their urine because their kidneys do not allow the
protein to leak through. If this mechanism is not working properly,
there will be excess levels of
protein in the urine. This is called
proteinuria.
The main
proteins that leak through are
albumin and globulin,
so proteinuria is
also sometimes referred to as
microalbuminuria.
According to
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, around 20% of CKD cats have
obvious proteinuria. and
50-66% do not have it. The remaining 14-30% are borderline.
Pet Place has a non-technical explanation of
proteinuria.
Chronic kidney disease
(2007) Polzin D
Delaware Valley Academy of Veterinary Medicine has some information
about proteinuria (page 17).
Why
Proteinuriais Important
Proteinuria is important because it may make the CKD progress faster.
Chronic kidney disease (CKD) in dogs and cats — staging and management
strategies
(2015) Chew D Presentation to the Virginia
Veterinary Medical Association 2015 Virginia Veterinary Conference states
"Protein in urine is both a marker and a creator of more renal disease."
Proteinuria
also plays an important role in the
early detection of CKD, and is used to
help diagnose and stage CKD
.
Types of Proteinuria
Proteinuria can have a number of possible causes, and t
reating
the cause (if possible) may mean the proteinuria resolves.
Treatment recommendations for CKD in cats
(2019) International Renal Interest Society
state "Cats in Stage 3 with urine protein to creatinine ratio (UP/C) >0.4 should
be investigated for disease processes leading to proteinuria...Look for
any concurrent associated disease process that may be treated/corrected”
The proteinuria is caused by the
kidneys not working properly.
Glomerulonephritis or
amyloidosis
may cause severe proteinuria, but
Electrophoretic patterns of proteinuria in feline spontaneous chronic
kidney disease
(2020) Giraldi M, Paltrinieri S & Scarpa P Journal
of Feline Medicine and Surgery 22(2) pp114-121 states "tubular proteins
were significiantly more frequent in our population of cats with CKD
compared with healthy cats at risk. This result supports the fact that the
main pathological feature of feline (idiopathic) CKD consists in chronic
tubular interstitial nephritis."
Post-Renal (Non-Renal)
The proteinuria is caused by a part of the urinary
tract other than the kidneys depositing protein in the urine.
Blood in the urine,
infection or inflammation may give a false positive result, causing
post-renal proteinuria.
It is not known exactly why proteinuria worsens kidney disease in cats.
Feline chronic kidney disease and the proteinuric
conundrum (2014) Sparkes A Presentation to the Australian
and New Zealand College of Veterinary Scientists Science Week 2014
states "It is thought, in humans at least, that proteins in the
tubular fluid (passing through a damaged glomerulus) provoke an
inflammatory response that produces further renal damage,
"
and it is possible that this also happens in cats.
Proteinuria (2013)
Syme H Presentation to the 38th World Small Animal Veterinary
Association World Congress states
"Following
loss of a critical amount of renal mass, hyperfiltration occurs in the
remaining functional nephrons. Hyperfiltration occurs due to an increase
in pressure applied to the glomerular filtration barrier, and this
results in proteinuria. Ultimately, over time, this adaptive change may
be detrimental ('maladaptive') and may result in interstitial fibrosis
and inflammation resulting in further nephron loss, even in the absence
of any extrinsic factors which damage the kidney (the so-called intact
nephron hypothesis).
Measurement and interpretation of proteinuria and
microalbuminuria (2016)
Grauer FG International Renal Interest Society states that the most commonly used method of
obtaining urine to check for proteinuria is via the urine dipstick test
but adds that "both routine-screening tests (dipstick and SSA) performed
poorly and appear to be of minimal diagnostic value due to an unacceptable
high number of false-positives. For both dipstick and SSA
tests, the positive and negative likelihood ratios were close to 1 and the
positive and negative predictive values were close to 50%, indicating that
neither test provided useful information."
Urine protein-to-creatinine concentration ratio in
samples collected by means of cystocentesis versus manual compression in
cats (2015)
Vilhena HC, Santos RR, Sargo TJ, Lima TB, Dias SS, Pastorinho MR, Queiroga
FL & Silvestre-Ferreira AC Journal of the American Veterinary
Medical
Association246(8) pp862-867 discusses whether the urine
collection method affects the accuracy of the result, and also found the
urine dipstick test was not particularly accurate, but mentions that
cystocentesis may cause blood in the urine, which in some cases may
adversely affect
the result.
Infection or
inflammation may also give a false positive result.
Urine
Protein:Creatinine Ratio (UPC)
The best way to test for proteinuria is via the
urine protein:creatinine (UPC) ratio, which is also used to determine the
severity of the proteinuria
(see
below).
The UPC test is available from
Idexx Laboratories,
which states "If the urinalysis is positive for protein and the sediment is not active,
a urine protein:creatinine (UPC) ratio is automatically performed. If the
urinalysis is negative for protein, or if there is an active sediment
(white blood cells =6/hpf, red blood cells = 100/hpf, color is red or
pink, and/or bacteria are seen), the UPC ratio will not be performed. The
test price is the same whether or not a UPC ratio is performed."
It is recommended that three urine samples should be collected over a
minimum period of two weeks before a conclusion is drawn as to the
diagnosis of proteinuria.
The
degree of proteinuria is usually indicated by the number of + signs on the
test result, with more + indicating greater severity, so Protein +++ is
more severe than Protein +.
Cornell University College of Veterinary Medicine
explains more about the diagnosis of proteinuria.
It says "The urine protein results should always be interpreted in context with
the urine specific gravity and pH. Normal urine contains little protein;
negative to trace reactions are usual in concentrated urine (urine
specific gravity > 1.025). A trace to 1+ reaction in a dilute urine
(urine specific gravity < 1.015) is suggestive of significant
proteinuria. A dipstick protein reaction > 2+ in concentrated or dilute
urine indicates significant proteinuria."
The importance of proteinuria and
microalbuminuria
(2006) Scott SA, Surdyk K & Brown C Presentation to the World Small
Animal Veterinary Association World Congress, discusses diagnostic
methods for proteinuria.
Treatment recommendations for CKD in cats (2019) International Renal Interest Society suggest a
biopsy
is also necessary for "Persistent and severe proteinuria (UP/C>2.0) in a
non-azotemic patient" or "Worsening proteinuria in a CKD patient."
Proteinuria
Staging and Prognosis
IRIS staging of CKD
(2019) International Renal Interest Society
uses
proteinuria as a risk factor for the development of CKD, and as one
factor in
determining the severity of the CKD. It does this by measuring the UPC
ratio, which is the ratio of protein (in the urine) to the cat's
creatinine level (in the blood).
Idexx Laboratories offers a
UPC test in a number of different countries. It is part of their catalyst 1 test.
IRIS grades the UPC ratio as follows:
Urine Protein: Creatinine Ratio
Proteinuria Status
Below 0.2
Non Proteinuric (NP)
Between 0.2 and 0.4
Borderline Proteinuric (BP)*
Over 0.4
Proteinuric (P)
*Check again within two months
Treatment recommendations for CKD in cats
(2019) International Renal Interest Society
state "Changes in the magnitude of proteinuria should always be interpreted in
light of the patient's blood creatinine concentration since proteinuria
may decrease in progressive renal disease as the number of functional
nephrons decrease. Decreasing proteinuria in the face of a stable blood
creatinine suggests improving renal function, whereas decreasing
proteinuria with increasing blood creatinine suggests disease
progression."
There is a correlation between the severity of proteinuria and the
prognosis.
Survival of cats with naturally occurring chronic renal
failure is related to severity of proteinuria
(2006) Syme
HM, Markwell PJ, Pfeiffer D & Elliott J Journal of Veterinary Internal
Medicine20 pp528–535
found that cats with a urine protein:creatinine ratio below 0.5 survived
almost three times as long as cats with a urine protein:creatinine ratio of
over 0.5.
However, do not panic if your cat's level is over 0.4 because the UPC
ratio is not always accurate — for example,
blood in the urine, infection or
inflammation may give a false positive result.
Hypertension
may worsen proteinuria, so getting blood pressure under
control may lead to an improvement in the UPC ratio.
The UPC ratio is
often higher if the cat has
glomerulonephritis.
Even if your cat's UPC ratio is indeed high, it may
gradually reduce with
treatment.
There are a number of possible treatments, some of
which can be quite effective at reducing the level of proteinuria, but as
yet there is little evidence that any of them may delay the progression of the
CKD.
Reassessment of "normal" values in dogs and cats
with chronic kidney disease (2019)
Grauer GF International Renal Interest Society says "Current
recommendations suggest that persistent proteinuria of renal origin of a
magnitude > UPC of 0.4 in cats and > 0.5 in dogs with azotemic CKD should
be treated with a renal diet and an angiotensin converting-enzyme
inhibitor (ACEI) or angiotensin receptor blocker (ARB). Borderline
proteinuria (UPC of 0.2 to 0.5 in dogs, or 0.2 to 0.4 in cats) warrants
increased monitoring. Note, however, that borderline and even "normal"
levels of proteinuria in cats have been associated with progressive
disease."
Assessment and management of proteinuria in dogs and
cats: 2004 ACVIM Consensus Statement (Small Animal)
(2005) Lees GE, Brown SA, Elliott J, Grauer GF & Vaden SL Journal of
Veterinary Internal Medicine19 pp377-385 gives suggestions for
the diagnosis and treatment of proteinuria. These guidelines are now quite
old, and whilst the basic information still applies, there is no
discussion of newer treatments such as telmisartan.
There
is as yet no evidence that these treatments will reduce proteinuria in
cats
but they are usually
helpful for a CKD cat for
other reasons (see
Nutritional
Requirements), so I would speak to your vet about trying them.
Feeding a
reduced
protein but high quality protein food may be
recommended.
Nutritional management of feline chronic kidney
disease
(2008) Elliott J,
Elliott D Veterinary Focus18(2) pp39-44 states that
"protein restriction may "decrease proteinuria mediated by glomerular
hyperfiltration, a mal-adaptive response to CKD which contributes to
progressive renal injury. This is the reason for reducing protein intake
in Stages 2 and 3 of CKD." However, the authors themselves admit that "The
efficacy of reducing protein intake as a treatment for proteinuria is
highly controversial in the cat and dog", adding that this may lead to
malnutrition.
High
dose omega 3 polyunsaturated fatty acids (n3 PUFAs) in the form of
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown
to reduce proteinuria in humans with glomerular disease. It is also
possible that renal eicosanoid production may be affected, reducing
inflammation and vasoconstriction; the n3 PUFAs are renoprotective in the
dog. Dogs consuming n3 PUFAs have lower mortality, increased renal
function, and reduced proteinuria and cholesterol. The dose of n3 PUFAs is
not known in dogs and cats and dosing is extrapolated from human data.
Prescription renal diets, however, are often supplemented with n3 PUFAs."
Stem Cell Transplants
Studies indicate that
stem cell transplants may improve proteinuria in rats with induced
kidney injury. There is as yet no evidence that they may do the same for
cats.
Medications
The following medications that may be used to treat
proteinuria:
ACE inhibitors are heart medications which are
commonly used to treat a heart condition called
hypertrophic cardiomyopathy. They work by preventing the conversion of
a hormone called angiotensin I into another hormone called angiotensin II,
that plays a part in the development of proteinuria. The role of
angiotensin II is to constrict blood vessels By preventing the conversion if
ACEI into ACEII, the ACE inhibitor thus relaxes the blood vessels, which
helps to reduce blood pressure and therefore reduces the work that the
heart has to perform to pump blood through the body. This may also reduce
proteinuria.
ACE inhibitors are sometimes used to control
hypertension (high blood pressure), and their use for this purpose is covered on the
Hypertension page, though they are not usually considered the best
choice for managing hypertension in cats.
The main reason they tend to be used i CKD cats is for reducing proteinuria.
One ACE inhibitor, benazepril, is
approved for the treatment of CKD in cats in
the UK, Europe, Australasia and Canada. If you are in these countries, it is
therefore highly likely that your vet will offer you this treatment at
some stage. Indeed, in the UK, benazepril and therapeutic kidney diets are often
the only treatments offered (though if they were all that is available or
suitable for CKD cats, this website would be a lot shorter than it is!).
Benazepril is sold under the trade names of
Fortekor
or Benazecare
in Europe and Canada and under the trade name of
Lotensin
in the USA. You do not want Fortekor Plus, because it also contains
another heart medication,
pimobendan.
Since in practice most people who are offered an ACE
inhibitor will be offered benazepril, much of what is stated below focuses
on this medication, particularly since almost all the research into the
use of ACE inhibitors in cats relates to benazepril.
Enalapril (trade name is Enacard) is another member
of the ACE inhibitor family. This is excreted largely by the kidneys, so
is not usually the best choice for a CKD cat. Benazepril, in contrast, is primarily
excreted (85%) via the liver in cats, which puts less strain on the
kidneys.
ACE inhibitors may improve proteinuria because they
block the negative effects of angiotensin II (see
above). This
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.
Chronic kidney disease (CKD) in dogs and cats — staging and management
strategies
(2015) Chew D A Presentation to the
Virginia Veterinary Medical Association 2015 Virginia Veterinary
Conference explains more about this on pages 10 and 11 (it is quite
technical).
Evaluation of the clinical efficacy of benazepril in
the treatment of chronic renal insufficiency in cats
(2006) Mizutani H, Koyama H, Watanabe T, Kitagawa H, Nakano M,
Kajiwara K & King JN Journal of Veterinary Internal Medicine
20(5) pp1074-9 tested benazepril on 61 cats with naturally occurring
CKD in a randomised double-blind placebo-controlled study. The study found
that UPC ratios
were significantly lower in cats given benazepril when
compared with cats given the placebo at days 120 and 180. "Incidence rates of cats with
IRIS classification stage 2 or stage 3 that remained in stage 2 or 3
without progressing to stage 4 were higher with benazepril (93 +/- 5%) as
compared with placebo (73 +/- 13%)."
Since ACE inhibitors may sometimes lead to an
increase in creatinine levels (usually temporary), some vets are reluctant
to use them in later stage CKD cats. ACE inhibitors and CKD: the good, bad and ugly
(2016) Grauer GF CVC in Kansas City
Proceedings pp670-672 says "Use of ACEI in dogs and cats with serum
creatinine concentrations greater than 5.0 mg/dl is usually not
recommended." However,
Treatment recommendations for CKD in cats
(2019) International Renal Interest Society
do not advise against using ACE inhibitors at any stage, saying "Cats
in Stage 4 with urine protein to creatinine ratio (UP/C) >0.4 should be
investigated for disease processes leading to proteinuria and treated with
anti-proteinuric measures."
Although ACE inhibitors do reduce proteinuria in
cats, it is not clear whether this makes a real difference to lifespan.
Tolerability and efficacy of benazepril in cats with
chronic renal disease (2006)
King JN,
Gunn-Moore DA,
Tasker S,
Gleadhill A &
Strehlau GJournal of Veterinary
Internal Medicine20(5) pp1054-1064 found that benazepril
improved proteinuria in cats in the study, and cats with more severe
proteinuria (a UPC
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 a therapeutic kidney diet only.
However, the study states "there was no difference in renal survival time
between the two groups when all 192 cats were compared."
Benazepril (Fortekor)
Dosing
Benazepril comes in tablet form in either 2.5 mg or
5 mg sizes.
When used to treat proteinuria in cats, the usual dose is
0.5 - 1.00 mg per kg of body weight once each day, so a 10 lb (4.5 kg) cat
would receive 2.25mg a day. In practice, the manufacturer recommends that it be
administered as follows:
Cat Weight
Number of 2.5mg tablets
2.5
- 5.0 kg (5.5 - 11 lbs)
1 tablet
5.0 - 10.0 kg (11 - 22 lbs)
2 tablets
In light of the cautions immediately below, it may be safer to start with
half the dose, only increasing gradually.
ACE
Inhibitor Cautions
Benazepril in the form of Fortekor has not been
tested in cats weighing less than 2.5kg (5 lbs) so be careful if you have
a small cat.
ACE Inhibitors and Increased Creatinine Levels
In some cats, creatinine levels may rise shortly after beginning
benazepril. Therefore the manufacturer of Fortekor
recommends that kidney bloodwork should be checked 5-10 days after
starting the medication, though very few vets seem to do this routinely. For most cats this increase
will be temporary, but monitor your cat to be sure. If your vet does not
think this is necessary, show him or her some of the following links.
General
guidelines for use of ACE-inhibitors in CKD include rechecking renal
function in 1 week following start of ACE-inhibition to make sure that
GFR has not been reduced too much. It is common to see a small increase
in serum creatinine at this time (20 to 30% increase over baseline). If
creatinine has increased too much, reduce the dose of the ACE-inhibitor.
Some dogs and cats are ACE-inhibitor intolerant in that their renal
function will be much worse during initial treatments so that treatment
must be discontinued. We also recommend to recheck the UPC 1 and 3
months after the start of ACE-inhibition. The goal is to achieve a 50%
decrease in UPC in those in which it was initially increased."
Therapeutic implications of recent findings in
feline renal insufficiency
(2009)
Scherk M Presentation to the International Congress of the Italian
Association of Companion Animal Veterinarians states "Cats with an increased UPC (> 0.4) who are started on this
medication, should be rechecked within 3-7 days and have their renal
parameters, hydration, body weight, appetite and overall health monitored.
Thereafter, re-evaluation should occur every 2-4 months in a stable
patient. If there is no decrease in UPC, the medication should be
discontinued."
ACE
Inhibitors and Dehydrated Cats
It is very important not to use ACE
inhibitors in dehydrated cats because doing so can push them over the
edge.
ACVIM consensus statement: guidelines for the
identification, evaluation and management of hypertension in dogs and cats (2018) Acierno MJ, Brown S, Coleman AE, Jepson RE, Papich M,
Stepien RL & Syme HM Journal of Veterinary Internal Medicine 32(6)
pp1803-1822 say
"Angiotensin converting
enzyme inhibitors and ARB
should not be started in dehydrated patients in which
GFR
[a measure of kidney function] may decrease precipitously.
These patients should be carefully rehydrated and then re-evaluated before
instituting ACEi or ARB treatment."
Treatment recommendations for CKD in cats
(2019) International Renal Interest Society warn
"The use of an RAAS inhibitor is contraindicated in any cat that is
clinically dehydrated or is showing signs of hypovolemia. Correct
dehydration before using these drugs otherwise glomerular filtration rate
may drop precipitously."
Proteinuria
(2013) Syme H Presentation to the 38th World Small Animal Veterinary
Association World Congress states "Treating cats that are severely azotaemic or that
have prerenal azotaemia with ACE-inhibitors may actually speed their
demise."
Despite this, I often
hear of British cats who have high kidney values being sent home with
benazepril after a session on intravenous fluids, but with no access to
sub-Qs. Please be careful if this applies to you, because your cat will
probably become dehydrated without sub-Qs.
ACE
Inhibitors Effects on Potassium Levels and Anaemia
The use of ACE inhibitors may lead to an
increase in potassium levels in the blood, which could be a risk in a cat who already has
high blood
potassium levels. Drugs
discusses this.
However,
Renal dysfunction in small animals
(2013) Brown SA Merck Veterinary Manual
states "If an ACE inhibitor is used in conjunction with a renal diet,
potassium should be carefully monitored. Hyperkalemia may develop,
particularly in Stage 4, and dietary change or dosage adjustment should be
considered if serum potassium exceeds 6.5 mEq/L."
Using ACE inhibitors at the same time as
diuretics
such as furosemide (Lasix),
whilst sometimes necessary in cats with heart disease,
can be dangerous. Mar
Vista
Vet has more information about this.
Non-steroidal anti-inflammatories
(NSAIDs),
including
meloxicam (Metacam),
may increase the effects of benazepril and reduce blood pressure too far, so do not give both medications to
your cat without checking with your vet first.
ACE inhibitors should be given two hours apart from
phosphorus binders,
because the binders may reduce the bioavailability of the ACE inhibitors.
Drugs has more information about this.
ACE inhibitors may cause lethargy, particularly when first begun. This may
be a sign that blood pressure has fallen too low, which in turn may lead
to an increase in creatinine levels as described above. Coughing may also
be seen. Some cats exhibit vomiting and/or reduced appetite. Diarrhoea may
also occur.
Pet Place
discusses benazepril, including possible side
effects.
Whether to Use ACE Inhibitors
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”.
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."
Although studies indicate that ACE inhibitors may
reduce proteinuria, they have not indicated an increase in survival time.
Feline chronic kidney disease and the proteinuric
conundrum (2014) Sparkes A Presentation to the Australian
and New Zealand College of Veterinary Scientists Science Week 2014
says "interventional treatment with
ACEIs, while reducing the degree of proteinuria has not yet been shown to
have a survival benefit."
Treatment recommendations for CKD in cats
(2019) International Renal Interest Society say
"there is at present no evidence that
intervention with anti-proteinuric drugs slows progression."
Chronic
kidney
disease
in
dogs
and
cats
II: Principles of
management (2010)
Maddison J & Syme H Irish Veterinary Journal63(2) pp106-9
states "There is evidence that use of ACE inhibitors (such as
benazepril)
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."
Some members of
Tanya's CKD 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
mg/dl (USA) or 310 µmol/L (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 (see above). If you are already using benazepril and you have any
concerns, please
talk to your vet.
Angiotensin II receptor blockers (ARBs) are heart
medications but they work in a slightly different way to
ACE inhibitors.
Angiotensin II is a hormone, the role of which is to
constrict blood vessels. It plays a role in the development of
proteinuria. ARBs work by blocking the
receptor to which angiotensin II attaches, thus relaxing the blood
vessels, which in turn helps to reduce blood pressure and therefore
reduces the work that the heart has to perform to pump blood through the
body. These medications are sometimes referred to as angiotensin II
receptor antagonists.
In human medicine ARBs tend to be used when ACE
inhibitors cannot be used for some reason.
Telmisartan (Semintra)
Telmisartan is an ARB. Its trade names
include Micardis in the USA and Semintra in Europe.
Telmisartan was
launched in Europe in September 2013 and in Canada in June 2014 under the
name of
Semintra as a
treatment for proteinuria in cats.
The
US Food and Drug Administration
states that
telmisartan under the trade name of Semintra was approved in the USA in
2018 for the treatment of hypertension in cats.
Drugs has some information about the use of this drug in
humans, as does
Patient UK.
Using
Angiotensin II Receptor Blockers
to Control Proteinuria
Telmisartan
under the trade name of
Semintra
was
approved in Europe
for the "reduction of proteinuria associated with
chronic kidney disease (CKD) in cats” in December 2012.
The European Medicines Agency
has some
information about the approval of Semintra, and mentions that in one field
trial of around six months duration involving 224 cats,
Comparison of efficacy of long-term treatment with
telmisartan and benazepril in cats with chronic kidney disease
(2015) Sent U, Gössl R, Elliott J, Syme HM, Zimmering T Journal
of Veterinary Internal Medicine29(6) pp1479-87, telmisartan
"proved to be noninferior to benazepril and significantly decreased
proteinuria relative to baseline at all assessment points whereas
benazepril did not."
Semintra comes in liquid form in a 30ml bottle, with
a 4mg/ml strength, i.e. each ml contains 4 mg of telmisartan. Therefore
you would give 0.25ml per kg of body
weight each day, so a 10 lb (4.5 kg) cat would receive 1.125ml a day. This
means the bottle would last for almost four weeks.
In light of the cautions immediately below, it may be safer to start with
half the dose, only increasing gradually.
Telmisartan can be given orally or mixed with food.
It takes effect within seven days.
Angiotensin II Receptor Blockers
Cautions, Interactions and Side Effects
The advice for ARBs is very similar to that for ACE
inhibitors:
Angiotensin II Receptor Blockers: Increased Creatinine Levels
Semintra package leaflet
says 'In a
European clinical field study, adverse events categorised as renal
disorder/insufficiency (includes cases of chronic renal failure, elevated
creatinine and/or blood urea nitrogen) were recorded in 3.6% of
telmisartan-treated cats and 1% of placebo-treated cats."
These are small percentages, but
caution should be exercised, as with benazepril.
Angiotensin II Receptor Blockers: Effects on Potassium Levels and Anaemia
Drugs states
"Hematologic side effects have included anemia," though this is rare.
CVMP assessment report for Semintra
(EMEA/V/C/002436)
(2012) discusses the approval of telmisartan for
proteinuric cats in Europe and states "Other effects were: reversible
increases in serum potassium; reversible increases in urea nitrogen and
creatinine; reversible decreases in red blood cell parameters; and
slightly elevated values for AST, ALT and bilirubin." These increases were
actually seen in dogs and rats, but it adds "Given the possibility for
effects on red blood cell parameters, the SPC includes a recommendation
that red cell count should be monitored during therapy."
Angiotensin II Receptor Blockers: Side Effects and Interactions
Prescribers' Digital Reference
says of
meloxicam (Metacam), a non-steroidal
anti-inflammatory (NSAID),
and telmisartan,
that NSAIDS "may alter the response to
Angiotensin II receptor blockers due to inhibition of vasodilatory
prostaglandins...In patients who are elderly, volume-depleted (including
those on diuretic therapy), or with compromised renal function who are
being treated with NSAIDs, coadministration of angiotensin II receptor
antagonists may result in further deterioration of renal function,
including acute renal failure. These effects are usually reversible."
Therefore I would
not give both medications to
your cat without checking with your vet first.
Whether to Use
Angiotensin II Receptor Blockers
Telmisartan (Semintra) has been available in Europe
since 2012 and in the USA since 2018, and like benazepril (Fortekor), some members of
Tanya's CKD Support Group
think it is helpful whilst others felt it did not
have any benefits.
As with benazepril, I would be prepared to use
telmisartan if I had a cat with
proteinuria, but until more research into ARBs in cats has been performed,
I don't think I would bother otherwise.
ACE Inhibitors or Angiotensin II Receptor Blockers
I am sometimes asked whether it is
better to use benazepril or telmisartan. There is a lot more research into
the use of benazepril in cats than there is into telmisartan. According to
CVMP assessment report for Semintra
(EMEA/V/C/002436)
(2012),
even the study on which the
approval of Semintra was based did not focus on its effectiveness as such,
but rather "was designed to show that telmisartan is as efficacious as the
comparator, the ACE inhibitor benazepril, to reduce proteinuria in CKD in
the cat."
Chronic kidney disease (CKD) in dogs and cats — staging and management
strategies
Chew D (2015) Presentation to the Virginia
Veterinary Medical Association 2015 Virginia Veterinary Conference states that
"It is not clear when or if an ARB
should be chosen to reduce RAAS activity instead of an ACE-Inhibitor for
treatment of CKD in veterinary patients to reduce proteinuria, systemic
blood pressure, or intrarenal inflammation."
Feline CKD: New horizons — where do we go from here?
(2013) Taylor S & Sparkes AH Journal of
Feline Medicine and Surgery15 Suppl 1 pp45-52
states "Despite some
potential advantages of the use of ARBs in human CKD, their efficacy
appears to be similar to that of ACE inhibitors, effected via a reduction
in glomerular capillary pressure and improvement in permselectivity of the
glomerular capillary barrier, and hence a reduction in proteinuria and
arrest of progression in proteinuric renal diseases. The use of ACE
inhibitors and ARBs in human CKD thus appears largely to be
interchangeable, with NICE guidelines in the UK not indicating a preferred
treatment." It adds that further research is necessary to
fully assess how useful telmisartan can be in cats.
However,
Attenuation of the pressor response to exogenous
angiotensin receptor blockers and benazepril hydrochloride in clinically
normal cats
(2015)
Jenkins TL, Coleman AE, Schmiedt CW & Brown SA American Journal of Veterinary Research76(9) pp807-13
compared the effectiveness of three
ARBs, including telmisartan, and benazepril. It concluded that "Results
indicated that telmisartan administration may have advantages over
benazepril administration for cats with renal or cardiovascular disease."
It should be noted that the medications were tested in only six healthy,
young cats.
Combining ACE Inhibitors and
Angiotensin II Receptor
Blockers
In humans, ACE inhibitors and ARBs are occasionally
used together, usually when the patient is on the maximum dose of an ACE
inhibitor but is still having problems such as proteinuria not being fully
controlled. However,
Health Canada
states (with regard to humans) "Recent studies have
demonstrated that any combination of aliskiren, ACEIs or ARBs increases
the risks of hypotension (low blood pressure), hyperkalemia (high levels
of potassium in the blood) and kidney problems."
Feline CKD: New horizons — where do we go from here?
(2013) Taylor S & Sparkes AH Journal of
Feline Medicine & Surgery15 Suppl 1 pp45-52 states "Studies will also be needed to see if
combined ACE inhibitor and ARB therapy may have additional benefits in
cats with CKD for control of blood pressure, control of proteinuria and
improved survival, as is seen in some humans with CKD. An increase in
adverse renal outcomes in some studies, however, means indications for
dual RAAS blockade remain controversial."
A human study,
Dual blockade of the renin-angiotensin system with angiotensin converting
enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)
(2011) Ritter JM British Journal of Clinical
Pharmacology 71(3) pp313–315, says that while a "trial of the
combination of telmisartan (ARB) with ramipril (ACE inhibitor) versus
monotherapy showed that combined therapy achieved a mean blood pressure
reduction 2.4/1.4 mm Hg greater in the combination group than in the group
treated with ramipril alone and a greater effect on urinary albumin
excretion, the combination showed no benefits in terms of the primary
study endpoint (a composite of cardiovascular death, myocardial
infarction, stroke and hospitalisation for heart failure), caused more
symptoms attributable to hypotension, and increased the decline
in renal function and need for dialysis compared with ACE inhibitor
monotherapy...Thus clinical endpoint evidence does not support combined
use of ACE inhibitor with ARB...Messerli concluded that ‘unless data emerge to the contrary, dual
blockade should no longer be used in clinical practice’."
Aspirin
Aspirin is sometimes recommended for
proteinuria, but it
can be toxic to cats, who can only
metabolise it very slowly. When it is used, aspirin is usually only given
in very low doses once every three days.
Treatment recommendations for CKD in cats
(2019) International Renal Interest
Society says "Cats with proteinuria and hypoalbuminemia likely share the same
thromboembolic risk as dogs, (although evidence is lacking in the
published literature), but aspirin is difficult to use in cats to achieve
a selective antiplatelet effect. A suggested dose rate if plasma albumin
is below 20 g/l (2 g/dl) is 1 mg/kg every 72 hours and an alternative to
aspirin is clopidogrel (10 to 18.75 mg/day)."
Beraprost (Rapros)
Beraprost sodium, made by
Toray Industries in Japan under the name of Rapros, which is approved for
the treatment of CKD in cats in Japan.
Medications in this family are
vasodilators, i.e. they relax the blood vessels.
This class of medication is commonly
used in humans to treat pulmonary arterial hypertension, though beraprost
is not the most effective drug for that purpose.
Nikkei Asian Review
reports that beraprost was
approved in Japan for the treatment of CKD in cats with effect from April
2017.
A double-blind placebo-controlled multicenter
prospective randomized study of beraprost sodium treatment for cats with
chronic kidney disease
(2018) Takenaka M, Iio A, Sato R,
Sakamoto T & Kurumatani H Journal of Veterinary Internal Medicine32(1) pp236-248 looked at the use of beraprost in CKD cats in 22
veterinary practices in Japan. The cats in the study had a USG below
1.035, creatinine over 1.6mg/dl (140 mmol/l) and a UPC ratio below 1.5.
After six months, creatinine and the phosphorus:calcium ratio increased in
the placebo cats but not in the cats receiving beraprost. The study found
that beraprost appears to be safe but "there was
no significant change
in the USG in either group."
The manufacturer of Rapros claims it
may slow the progression of CKD. At present the jury is out on whether ACE
inhibitors and ARBs can do this and I think the same probably applies to
Rapros.
I am not aware of any plans to launch
Rapros outside the Japanese market.
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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