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Early Detection

Share This Site: A Notice for Your Vet's Bulletin Board or Your Local Pet Shop

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.

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 Surgery 18 pp219-239, around 20% of CKD cats have obvious proteinuria. and 50-66% do not have it. The remaining 14-30% are borderline.

Proteinuria can have a number of possible causes, and treating 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”

Pre-Renal

Renal

Post-Renal (Non-Renal)

Whatever the precise mechanism, clearly it is important to know about and treat proteinuria.

Diagnosis

Proteinuria is diagnosed via a urine sample. See Diagnosis for more information about obtaining urine samples.

Proteinuria and renal disease: a roundtable discussion (2005) is an interesting discussion by a number of veterinary specialists about proteinuria, and CKD generally, that includes a diagnostic algorithm.

Investigating proteinuric kidney disease (2007) Polzin D Veterinary Medicine discusses the significance of proteinuria.

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 Association 246(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.

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.

An update on the diagnosis and management of proteinuria in dogs and cats (2018) Idexx Laboratories has a very helpful overview of proteinuria and provides codes for its tests.

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."

Cut out and keep guide...diagnostic implications of proteinuria (2013) van Dongen A Veterinary Focus 23(3) pp47-48 explains more about the diagnosis of proteinuria.

Role of quantitative MA testing in everyday practice (2012) Harai B Antech Insights Aug/Sep 2012  discusses how to run and interpret tests 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."

*Check again within two months

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."

The following medications that may be used to treat proteinuria:

• ACE inhibitors, including benazepril (Fortekor) or enalapril (Enacard)

  Angiotensin II receptor blockers (ARBs), such as telmisartan (Semintra)

  • Which to use

  • Combining ACE inhibitors and ARBs

• Aspirin

• Beraprost (Rapros)

ACE Inhibitors

• What are ACE inhibitors?

• Using ACE inhibitors to control proteinuria

• Cautions, interactions and side effects

• Whether to use ACE inhibitors

What are ACE Inhibitors?

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.

Angiotensin converting enzyme (ACE) inhibitors (2017) Klabunde RE Cardiovascular Pharmacology Concepts explains how ACE inhibitors work.

Benazepril (Fortekor, Benazecare, Lotensin, Nelio)

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.

Pet Place has some information about benazepril.

Enalapril (Enacard)

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).

Proteinuria in cats with chronic kidney disease (2008) Langston CE Veterinary Medicine is a video presentation (video may no longer work properly). Dr Langston starts benazepril if  the UPC ratio is over 0.4.

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 G Journal of Veterinary Internal Medicine 20(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:

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.

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.

Tolerability and efficacy of benazepril in cats with chronic renal disease (2006) King JN, Gunn-Moore DA, Tasker S, Gleadhill A & Strehlau G Journal of Veterinary Internal Medicine 20(5) pp1054-1064 found that "benazepril had no relevant effect on plasma potassium concentrations and in particular did not contribute to hyperkalemia."

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."

Treatment recommendations for CKD in cats (2019) International Renal Interest Society advise against the use of ACE inhibitors when potassium is over 5 mEq/L.

There is some debate as to whether ACE inhibitors may exacerbate anaemia and/or induce some resistance to the use of erythropoiesis stimulating agents (Aranesp, Epogen, Procrit or Eprex) in humans. The role of ACE inhibitors and angiotensin II receptor blockers in the response to epoetin (1999) MacDougall IC Nephrology Dialysis Transplantation 14(8) pp1836-1841 reports on the evidence for and against this concern in humans.

ACE Inhibitors Interactions and Side Effects

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.

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 Journal 63(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)

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.

An American vet school investigated the use of telmisartan to control blood pressure. 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 Medicine 29(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."

Telmisartan (Semintra) Dosing

The advice for ARBs is very similar to that for ACE inhibitors:

Angiotensin II Receptor Blockers: Increased Creatinine Levels

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

Feline CKD: New horizons — where do we go from here? (2013) Taylor S & Sparkes AH Journal of Feline Medicine and Surgery 15 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 Research 76(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.

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