Proteinuria

Proteinuria means there is excess protein in the urine. In a healthy cat, the kidneys act as a precise filter, allowing almost no protein to pass through. When that filter breaks down, protein leaks into the urine, and this is a problem worth taking seriously.

Proteinuria matters for two main reasons: it is used to help stage chronic kidney disease (CKD), and it may cause CKD to progress faster. Around 20% of cats with CKD have clear proteinuria. Another 14 to 30% fall in a borderline range. The remaining 50 to 66% do not have it at all.

This page explains what proteinuria is, how it is diagnosed, what the results mean, and what can be done about it.

In a healthy cat, the kidneys prevent protein from leaking into the urine. If the filtration system is not working properly, protein passes through, and proteinuria is the result.

The proteins most commonly involved are albumin and globulin, which is why proteinuria is sometimes called microalbuminuria in the early stages.

Protein in the urine is both a warning sign and an active driver of further kidney damage. It is used in early detection of CKD and plays a role in staging the disease through the IRIS (International Renal Interest Society) system. If proteinuria is present alongside CKD, addressing it becomes an important part of management.

Proteinuria has several possible causes, and identifying the type helps guide treatment.

Pre-renal proteinuria originates outside the kidneys. Hypertension, hyperthyroidism, and acute pancreatitis are among the possible causes. If the underlying condition is treated, the proteinuria may resolve.

Renal proteinuria is caused by the kidneys themselves not working properly. It is further divided into glomerular, tubular, and interstitial subtypes depending on where in the kidney the protein is leaking from. Tubular proteinuria is thought to be the most common form in cats with CKD, reflecting the chronic tubular interstitial nephritis that characterises feline kidney disease. A condition called protein-losing nephropathy (PLN), more often associated with dogs, has been found to occur in cats more frequently than previously assumed, particularly in younger male cats with a higher UPC ratio.

Post-renal proteinuria originates in the urinary tract beyond the kidneys. Blood in the urine, infection, or inflammation can all cause a false positive result. This is one reason results should always be interpreted carefully and retested before drawing conclusions.

The precise mechanism is still being studied, but there are several ways proteinuria is thought to worsen kidney function.

When protein passes through a damaged glomerulus into the tubular fluid, it can trigger an inflammatory response that causes further kidney damage. This is well established in humans and is thought to operate similarly in cats.

A process called hyperfiltration also plays a role. When enough nephrons are lost, the remaining ones compensate by increasing their filtration pressure. Over time, this increased pressure damages the glomerular filtration barrier, causing proteinuria. The proteinuria then contributes to interstitial fibrosis and inflammation, which leads to further nephron loss, even without any new external cause of injury.

More specifically, protein in the urine may damage the kidneys by overwhelming the proximal tubule cells that would normally reabsorb it, leaking into the interstitial space and triggering inflammatory cascades, and blocking tubules, causing them to be lost.

The most commonly noted symptom is foamy urine. Proteinuria can also cause weight loss and, in more severe cases, swelling in the legs, abdomen, or face.

Proteinuria is identified through urine testing. The urine dipstick test is the most common screening method, but it has significant limitations. Research has found that dipstick and SSA tests both have a high rate of false positives, making them of limited diagnostic value on their own.

The presence of blood in the urine, infection, or inflammation can all produce a false positive, so context matters. The urine collection method also affects results. Cystocentesis (collection directly from the bladder) is generally preferred, though it can occasionally introduce a small amount of blood, which may affect the reading.

Because individual results can vary, IRIS guidelines recommend collecting at least three urine samples over a minimum of two weeks before drawing conclusions about proteinuria. When monitoring proteinuria over time, it is also advisable to use the same laboratory for all tests, as a meaningful percentage of cats are assigned a different IRIS substage depending on which lab processes the sample.

The urine protein-to-creatinine (UPC) ratio is the most reliable way to assess proteinuria. It measures the ratio of protein in the urine to creatinine in the blood, giving a more accurate picture than a dipstick result alone.

IRIS uses the UPC ratio to classify proteinuria as follows:

 

Borderline results should be rechecked within two months. Cats with a UPC above 0.4 in IRIS Stage 3 or Stage 4 should be investigated for underlying conditions contributing to the proteinuria and treated accordingly.

One important nuance: proteinuria can decrease as CKD progresses, simply because fewer functional nephrons remain to leak protein. Falling proteinuria alongside rising creatinine suggests disease progression rather than improvement. Falling proteinuria with stable creatinine is a better sign.

A kidney biopsy may be recommended in cases of persistent, severe proteinuria (UPC above 2.0) in a non-azotemic cat, or when proteinuria is worsening.

The severity of proteinuria has a meaningful effect on survival time. Cats with a UPC ratio below 0.5 have been found to survive almost three times as long as cats with a ratio above 0.5.

In cats with PLN, younger male cats with a higher UPC ratio have been found to have a poorer prognosis, with a median survival time of around 94 days in one study.

That said, a high UPC result should not cause immediate alarm. False positives are common, and results often improve with treatment, particularly when hypertension is brought under control. Hypertension is known to worsen proteinuria, so addressing blood pressure can reduce the UPC ratio on its own.

Several treatments are available to reduce proteinuria. As yet, there is limited evidence that any of them can definitively slow the progression of CKD, but reducing proteinuria remains a worthwhile goal given the damage it can cause.

Current IRIS guidance recommends treating persistent proteinuria of renal origin with a UPC above 0.4 using a renal diet alongside either an ACE inhibitor or an ARB. Borderline proteinuria warrants closer monitoring rather than immediate treatment.

Feeding a reduced-protein but high-quality protein diet is sometimes recommended for cats with significant proteinuria. The rationale is that reducing protein intake may decrease the glomerular hyperfiltration that drives proteinuria in CKD. However, the evidence for this in cats is contested, and excessive protein restriction carries risks of malnutrition.

Omega-3 fatty acid supplementation has shown benefits in humans with glomerular disease and appears to be renoprotective in dogs, with studies showing reduced proteinuria and improved survival. The correct dosing for cats has not been established, though many prescription renal diets include added omega-3s.

ACE (angiotensin-converting enzyme) inhibitors block the conversion of angiotensin I into angiotensin II, a hormone that constricts blood vessels and contributes to the development of proteinuria. By reducing intraglomerular pressure, ACE inhibitors can reduce the amount of protein leaking through the damaged filtration barrier.

Benazepril (Fortekor, Benazecare, Lotensin, Nelio) is the ACE inhibitor most commonly used in cats. It is approved for CKD treatment in the UK, Europe, Australasia, and Canada. In the USA, ACE inhibitors tend to be reserved for cats with significant proteinuria or hypertension uncontrolled by amlodipine alone.

Benazepril is primarily excreted via the liver in cats (around 85%), which makes it a better choice than enalapril, which is excreted by the kidneys and therefore puts more strain on a compromised system.

Benazepril dosing: The usual dose is 0.5 to 1.0 mg per kg of body weight once daily. For a 4.5 kg (10 lb) cat, this works out to roughly 2.25 mg per day. Benazepril comes in 2.5 mg and 5 mg tablets. Starting with a lower dose and increasing gradually is advisable.

Monitoring: Because ACE inhibitors can cause a temporary rise in creatinine in some cats, bloodwork should be checked 5 to 10 days after starting the medication. A small increase of 20 to 30% is not unusual and is often temporary, but it should be monitored. The UPC ratio should be checked at one and three months after starting treatment. The goal is a 50% reduction in UPC.

Key cautions:

ACE inhibitors should not be used in dehydrated cats, as they can cause a precipitous drop in glomerular filtration rate in this situation. Any dehydration should be corrected before starting treatment.

IRIS advises against ACE inhibitor use when potassium is above 5 mEq/L.

Non-steroidal anti-inflammatories (NSAIDs) such as meloxicam may amplify the blood pressure-lowering effect of ACE inhibitors, so both should not be given together without veterinary guidance.

ACE inhibitors should be given two hours apart from phosphorus binders, as the binders can reduce the bioavailability of the ACE inhibitor.

Common side effects include lethargy, especially when first starting treatment (which may indicate blood pressure has fallen too low), and occasionally vomiting, reduced appetite, or diarrhoea.

Evidence: Controlled studies have found that benazepril reduces UPC ratios significantly compared to placebo. In one study, cats with severe proteinuria (UPC above 1.0) receiving benazepril showed improved appetite, weight gain, and a median survival time of 402 days versus 126 days for those on a therapeutic kidney diet alone. However, when all cats were included regardless of proteinuria severity, there was no statistically significant difference in overall survival time. IRIS notes that there is currently no direct evidence that ACE inhibitors slow CKD progression.

ARBs work differently from ACE inhibitors. Rather than blocking the production of angiotensin II, they block the receptor to which angiotensin II attaches. The end result is similar: blood vessel relaxation, reduced blood pressure, and reduced intraglomerular pressure.

Telmisartan (Semintra) is the ARB approved for use in cats. In Europe and the UK, it is approved for reducing proteinuria associated with CKD. In the USA, it is approved for the treatment of hypertension in cats. The two indications use different doses.

Semintra is a liquid, available as a 4 mg/ml solution in a 30 ml bottle. The dose for proteinuria is 1 mg per kg of body weight once daily, which works out to 0.25 ml per kg. A 4.5 kg (10 lb) cat would receive approximately 1.125 ml per day, making one bottle last roughly four weeks. Starting at a lower dose and increasing gradually is advisable.

Telmisartan can be given orally or mixed with food and takes effect within around seven days.

One clinical study found that telmisartan was not inferior to benazepril and significantly reduced proteinuria from baseline at all assessment points, while benazepril did not reach statistical significance. This led to its European approval, though it is worth noting the study was designed to demonstrate non-inferiority rather than superiority.

Cautions for ARBs are similar to those for ACE inhibitors. In cats with severe kidney disease, ARBs may reduce glomerular filtration rate, so renal function should be monitored. NSAIDs may reduce the antihypertensive effect and worsen renal function when used alongside ARBs in vulnerable cats. Reversible increases in creatinine, potassium, and urea nitrogen have been observed in some studies. Red blood cell parameters should also be monitored.

Both drug classes reduce intraglomerular pressure and lower proteinuria through related but distinct mechanisms. There is considerably more research on benazepril in cats than on telmisartan, but available evidence suggests their efficacy in reducing proteinuria is broadly similar.

One study comparing telmisartan and benazepril in healthy young cats found telmisartan may have advantages in cats with renal or cardiovascular disease, though the study was small. IRIS guidance does not currently express a preference between the two.

Combining ACE inhibitors and ARBs is occasionally used in humans when monotherapy is insufficient, but the evidence for this approach in cats is limited and the risk of hypotension, hyperkalemia, and worsening renal function is a concern. IRIS does not recommend dual RAAS blockade at this time.

Severe proteinuria, particularly in cats with protein-losing nephropathy, can increase the risk of thromboembolism. While this complication is better documented in dogs, cats with proteinuria and low albumin levels are thought to share a similar risk.

IRIS recommends clopidogrel (10 to 18.75 mg per day) as the drug of choice if antithrombotic treatment is needed. Aspirin is not reliably effective in cats and can be toxic because cats metabolise it very slowly. When aspirin is used, it is generally given only in very low doses every three days.

Beraprost sodium is a prostacyclin analogue approved for the treatment of CKD in cats in Japan, under the name Rapros. It is a vasodilator and has been studied for its potential renoprotective effects.

A controlled study in CKD cats found that creatinine and the phosphorus-to-calcium ratio increased in the placebo group but not in cats receiving beraprost over six months. A later analysis found an association between beraprost use and improved overall survival in cats with CKD in real-world practice, though the authors noted that a randomised controlled trial is needed to confirm these findings.

The manufacturer suggests it may slow CKD progression, but the evidence base is still developing. Rapros is not currently available outside Japan.

Giraldi M, Paltrinieri S & Scarpa P (2020). Electrophoretic patterns of proteinuria in feline spontaneous chronic kidney disease. Journal of Feline Medicine and Surgery 22(2), 114-121.

Grauer GF (2024). Measurement and interpretation of proteinuria and microalbuminuria. International Renal Interest Society.

Grauer GF (2024). Reassessment of “normal” values in dogs and cats with chronic kidney disease. International Renal Interest Society.

International Renal Interest Society (2023). IRIS staging of CKD.

International Renal Interest Society (2023). IRIS treatment recommendations for CKD in cats.

Ito H, Matsuura T & Sano T (2023). Beraprost and overall survival in cats with chronic kidney disease. Veterinary Science 10(7), 459.

Jenkins TL, Coleman AE, Schmiedt CW & Brown SA (2015). Attenuation of the pressor response to exogenous angiotensin receptor blockers and benazepril hydrochloride in clinically normal cats. American Journal of Veterinary Research 76(9), 807-813.

King JN, Gunn-Moore DA, Tasker S, Gleadhill A & Strehlau G (2006). Tolerability and efficacy of benazepril in cats with chronic renal disease. Journal of Veterinary Internal Medicine 20(5), 1054-1064.

Mizutani H, Koyama H, Watanabe T, Kitagawa H, Nakano M, Kajiwara K & King JN (2006). Evaluation of the clinical efficacy of benazepril in the treatment of chronic renal insufficiency in cats. Journal of Veterinary Internal Medicine 20(5), 1074-1079.

Mortier F, Daminet S, Duchateau L, Demeyere K, Meyer E & Paepe D (2023). Effect of laboratory and sample storage factors on urinary protein:creatinine ratios and clinical decision making in cats. Journal of Veterinary Internal Medicine 37(3), 1038-1046.

Rayhel LH, Quimby JM, Cianciolo RE, Cléroux A, McLeland SM & Franken T (2020). Clinicopathologic and pathologic characteristics of feline proteinuric kidney disease. Journal of Feline Medicine and Surgery 22(12), 1219-1229.

Schmid SM (2022). When urine trouble: a clinical approach to proteinuria. Today’s Veterinary Practice Jan/Feb 2022.

Sent U, Gössl R, Elliott J, Syme HM & Zimmering T (2015). Comparison of efficacy of long-term treatment with telmisartan and benazepril in cats with chronic kidney disease. Journal of Veterinary Internal Medicine 29(6), 1479-1487.

Sparkes AH (2014). Feline chronic kidney disease and the proteinuric conundrum. Presentation to the Australian and New Zealand College of Veterinary Scientists Science Week 2014.

Sparkes AH, Caney S, Chalhoub S, Elliott J, Finch N, Gajanayake I, Langston C, Lefebvre H, White J & Quimby J (2016). ISFM consensus guidelines on the diagnosis and management of feline chronic kidney disease. Journal of Feline Medicine and Surgery 18, 219-239.

Syme H (2013). Proteinuria. Presentation to the 38th World Small Animal Veterinary Association World Congress.

Takenaka M, Iio A, Sato R, Sakamoto T & Kurumatani H (2018). A double-blind placebo-controlled multicenter prospective randomized study of beraprost sodium treatment for cats with chronic kidney disease. Journal of Veterinary Internal Medicine 32(1), 236-248.

Vilhena HC, Santos RR, Sargo TJ, Lima TB, Dias SS, Pastorinho MR, Queiroga FL & Silvestre-Ferreira AC (2015). Urine protein-to-creatinine concentration ratio in samples collected by means of cystocentesis versus manual compression in cats. Journal of the American Veterinary Medical Association 246(8), 862-867.