Proteinuria in Dogs and Cats: Diagnosis and Management

Adapted from the IRIS education article "Measurement and interpretation of proteinuria and albuminuria" by GF Grauer (Manhattan, KS, USA), revised 2022.

Introduction

Persistent proteinuria with an inactive urine sediment is a marker of chronic kidney disease (CKD) in dogs and cats (reference 1). Evidence also suggests an association between renal proteinuria and the progression of CKD in both species: the greater the proteinuria, the greater the risk of kidney disease progression and death (references 2 to 5). Importantly, treatments that reduced proteinuria in dogs and cats with CKD may also have been associated with slower progression of kidney disease or improved survival (references 4 to 8). For these reasons, screening for renal proteinuria and monitoring it over time have received renewed interest.

Proteinuria is a general term for the presence of any type of protein in the urine, such as albumin, globulins, and Bence Jones proteins. Proteinuria of renal origin results from two main mechanisms: loss of selective glomerular filtration, which increases the amount of plasma protein in the filtrate, and impaired tubular reabsorption of the filtered protein. Albumin is the main protein in the urine of dogs and cats, in both health and kidney disease.

Normal Physiology

The urine of healthy dogs and cats contains only a small amount of albumin (less than 1 mg/dL) and other proteins. Type IV collagen in the basement membrane of the glomerular capillary wall restricts the filtration of most plasma proteins, mainly on the basis of molecular weight and size. Because of this selective permeability, albumin (molecular weight 69,000 daltons) and larger proteins are normally not present in large amounts in the glomerular filtrate. The negative charge of the glomerular capillary wall further hinders the passage of negatively charged proteins such as albumin. The initial glomerular filtrate of healthy dogs and cats contains only 2 to 3 mg/dL of albumin, compared with about 4 g/dL in plasma.

Smaller proteins, and the positively charged larger proteins that do pass through the glomerular capillary wall, are almost completely reabsorbed by the tubular epithelial cells, which may break them down and use them or return them to the plasma as amino acids. This reabsorption occurs mainly in the proximal convoluted tubules and reduces the albumin concentration in normal urine to less than 1 mg/dL. However, tubular reabsorption of protein has a transport maximum. Tubular proteinuria may occur if that maximum is exceeded, for example by excessive production of small proteins such as Bence Jones proteins, or if damage to the tubular cells, for example nephrotoxic damage or chronic tubulointerstitial disease, reduces their capacity to reabsorb protein.

Detection of Proteinuria

The urine dipstick colorimetric test is the usual first-line screening test for proteinuria and albuminuria, but false-positive reactions are common. Many laboratories confirm a positive dipstick result for protein with the sulfosalicylic acid (SSA) turbidimetric test. Proteinuria detected by dipstick or SSA screening, and thought to be of renal origin, is usually confirmed and quantified with the urine protein-to-creatinine ratio (UPC). The dipstick, SSA, and UPC tests are more sensitive for albumin than for other proteins. Species-specific tests can also detect albumin concentrations as low as 1 mg/dL in canine and feline urine.

The Dipstick Test

The dipstick test for proteinuria is inexpensive and easy to use and mainly measures albumin, but its sensitivity and specificity are relatively low. False-negative results (reduced sensitivity) can occur with Bence Jones proteinuria, low concentrations of albumin, and dilute or acidic urine. The lower limit of detection of the conventional dipstick is about 30 mg/dL. False-positive results are also common in both species, and more frequent in cats than in dogs. For example, when 599 canine and 347 feline urine samples from apparently healthy animals were analyzed with conventional urine protein test strips and with a canine or feline albumin-specific quantitative ELISA, the results differed. The sensitivity of the test strips for albuminuria (a trace or stronger reaction) was 81% in dogs and 90% in cats, but the specificity was only 48% and 11%, respectively (reference 9).

The Sulfosalicylic Acid Test

The SSA test is performed by mixing equal volumes of urine supernatant and 3% to 5% SSA in a glass test tube and grading the cloudiness caused by precipitated protein on a scale of 0 to 4+. As well as albumin, the SSA test detects globulins and Bence Jones proteins better than the dipstick test does. False-positive results may occur if the urine contains radiographic contrast agents, penicillin, cephalosporins, sulfisoxazole, or thymol (a urine preservative), and for other, unknown reasons. Protein content may also be overestimated if uncentrifuged, cloudy urine is tested. The reported sensitivity of the SSA test is about 5 mg/dL. Because of the relatively poor specificity of the dipstick, many reference laboratories confirm a positive dipstick result with the SSA test. In urine from apparently healthy dogs and cats, the sensitivity of the SSA test for albuminuria (a trace or stronger reaction) was 73% and 58%, respectively, but the specificity was only 64% and 25%, respectively (reference 9).

Interpreting the Screening Tests

Based on the same study, in canine urine a dipstick or SSA result of 2+ or more means there is a high probability that the sample contains albumin (reference 9). However, if the dipstick result is trace or 1+, an SSA test should be performed to confirm proteinuria. When both tests are performed at the same time, they should be interpreted in series, meaning both must be positive for the sample to be considered positive for albuminuria, rather than in parallel, to increase specificity. If both the dipstick and SSA results are in the trace to 1+ range, a positive result should be confirmed with a more specific test, such as an ELISA-based albuminuria test (reference 9).

For feline urine samples, both routine screening tests (dipstick and SSA) performed poorly and appear to be of minimal diagnostic value because of an unacceptably high number of false positives. For both 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 (reference 9). Based on these data, albumin in cat urine should always be measured with a better assay, such as the species-specific albuminuria ELISA.

The sensitivity and specificity of the dipstick and SSA tests for albuminuria have also been evaluated in cats with CKD, in which higher urine albumin concentrations or more frequent albuminuria would be expected to make the screening tests perform better (reference 10). In 239 urine samples from 37 cats with CKD, the sensitivity and specificity were 81% and 68% for a dipstick reaction above trace, and 63% and 96% for an SSA reaction above 5 mg/dL. A positive dipstick (trace or stronger) together with a positive SSA (5 mg/dL or more), a positive SSA alone, or a dipstick of 2+ or more alone indicated albuminuria, and in these cases quantifying the protein with a UPC is warranted. When the dipstick was negative, adding the SSA test added little diagnostic value (reference 10).

Proteinuria detected by these semi-quantitative screening methods has traditionally been interpreted in light of the urine specific gravity and urine sediment. For example, a trace or 1+ dipstick reading in concentrated (hypersthenuric) urine has often been attributed to the urine's concentration rather than to abnormal proteinuria, and a positive dipstick reading for protein in the presence of blood (hematuria) or white blood cells (pyuria) was often attributed to urinary tract hemorrhage or inflammation. In both situations, this interpretation may be wrong. Given the limited sensitivity of the conventional dipstick, any positive result for protein may be abnormal, whatever the urine concentration, apart from false-positive results. Likewise, hematuria and pyuria have an inconsistent effect on urine albumin: not all dogs with microscopic hematuria and pyuria have albuminuria (reference 11). When there is visible blood in the urine or microscopic pyuria, the source of the bleeding or inflammation should be diagnosed and treated before the proteinuria is assessed further.

Detection of Albuminuria

Albuminuria can be measured by quantitative immunoassays at reference laboratories. Microalbuminuria (MA) is defined as a urine albumin concentration above normal (more than 1.0 mg/dL) but below the limit of detection of conventional dipstick screening (30 mg/dL or less). Urine albumin concentrations above 30 mg/dL are called overt albuminuria. Urine albumin concentrations can be adjusted for differences in urine concentration by dividing by the urine creatinine concentration; for example, a urine albumin-to-creatinine ratio above 0.03 is considered abnormal in people. Alternatively, urine can be diluted to a standard concentration using the urine specific gravity (for example, 1.010) before the assay. In one study of dogs, normalizing urine albumin to a specific gravity of 1.010 gave results similar to the urine albumin-to-creatinine ratio (reference 12).

Microalbuminuria tests are indicated:

  • When conventional screening tests for proteinuria give equivocal or conflicting results, or false-positive results are suspected
  • When conventional screening tests are negative in apparently healthy older dogs and cats and a more sensitive screening test is wanted
  • When conventional screening tests are negative in apparently healthy young dogs and cats with a family risk of proteinuric kidney disease and a more sensitive screening test is wanted
  • When conventional screening tests are negative in dogs and cats with chronic illnesses often associated with proteinuric kidney disease and a more sensitive screening test is wanted
  • When previous microalbuminuria tests were positive, for monitoring over time

Interpretation and follow-up of microalbuminuria testing are critical. Like other tests for proteinuria, these tests can be affected by lower urinary tract inflammation, so the patient's history and urine sediment findings must be considered. A negative result is useful because it removes any concern about albuminuria until the next test. A positive result is more complex and needs to be confirmed by testing again about 7 to 10 days later. If the second test is negative, the first positive result was probably due to transient benign or physiological albuminuria that is unlikely to have long-term consequences. If follow-up tests remain positive, more frequent monitoring and further investigation are needed to confirm whether the proteinuria is persistent and to track changes in its severity. Increasing microalbuminuria probably indicates active, ongoing kidney injury and should prompt a search for infectious, inflammatory, or neoplastic disease that might be causing the kidney disease.

Causes of Albuminuria

In people, persistent albuminuria reflects intraglomerular hypertension or generalized vascular damage and endothelial dysfunction (reference 13). Interestingly, low-level albuminuria accurately predicts later kidney disease in people with systemic hypertension and diabetes mellitus, and it has also been observed in patients with systemic diseases associated with glomerular disease (references 14 to 18). Importantly, early detection of albuminuria and appropriate treatment have slowed the progression of kidney disease in people (reference 19).

A limited number of studies in dogs suggest that low-level albuminuria is a good indicator of early kidney disease (references 12, 20, and 21). As well as primary kidney disease, other conditions have been reported in dogs with albuminuria, including infectious, inflammatory, neoplastic, metabolic, and cardiovascular diseases (references 22 and 23). A study of albuminuria in dogs with lymphoma and osteosarcoma showed that urine albumin was significantly increased in dogs with these tumors, even though their UPC might not be increased above the reference range (reference 24). However, urine albumin did not consistently decrease as the tumor burden decreased.

The prevalence of low-level albuminuria in dogs admitted for intensive care is higher than in other reported populations and appears to vary with the type of disease (references 22 and 23). As in people with acute inflammatory conditions, some of these dogs had transient albuminuria. A large percentage of the dogs that were euthanized or died had albuminuria, suggesting that, as in people, it may be a negative prognostic indicator. Short-term prednisone treatment has been shown to cause a substantial but reversible increase in proteinuria and albuminuria in heterozygous (carrier) female dogs with X-linked hereditary nephropathy (reference 25). Finally, a moderate amount of exercise (20 minutes on a treadmill) did not affect albuminuria in dogs (reference 26).

Localization of Proteinuria

When screening tests detect proteinuria or albuminuria, it is important to try to identify its source. Proteinuria may be physiological or pathological. Physiological (benign) proteinuria is often transient and resolves when the underlying cause is corrected. Examples of conditions that may cause physiological proteinuria are strenuous exercise, seizures, fever, exposure to extreme heat or cold, and stress. The mechanism is not completely understood, but transient narrowing of the kidney's blood vessels, reduced blood flow, and congestion may be involved. Reduced physical activity may also affect urine protein excretion in dogs: one study found that urinary protein loss was higher in dogs confined to cages than in dogs with normal activity (reference 27).

Pathological proteinuria may be caused by abnormalities inside or outside the urinary tract. Disorders outside the urinary tract that are associated with proteinuria often involve the production of small proteins (dysproteinemias) that are filtered by the glomeruli and overwhelm the reabsorptive capacity of the proximal tubules. An example of this "pre-renal" proteinuria is the production of immunoglobulin light chains (Bence Jones proteins) by neoplastic plasma cells. Inflammation of the genital tract, such as prostatitis or metritis, can also cause proteinuria from outside the urinary tract. Collecting urine by cystocentesis reduces the chance of contamination with protein from the lower urinary tract.

Pathological proteinuria from the urinary tract may be renal or non-renal in origin. Non-renal proteinuria most often occurs with lower urinary tract inflammation or hemorrhage, and is also called post-renal proteinuria. The urine sediment usually shows changes consistent with the underlying inflammation, such as white blood cells, red blood cells, bacteria, or increased numbers of transitional epithelial cells. Renal proteinuria, on the other hand, is most often caused by increased glomerular filtration of plasma proteins associated with intraglomerular hypertension or with immune complexes, amyloid, or vascular inflammation in the glomerular capillaries. It may also be caused by reduced reabsorption of filtered plasma proteins because of tubulointerstitial disease. In some cases, tubulointerstitial proteinuria is accompanied by glucose in the urine despite normal blood glucose and by increased excretion of electrolytes, as in Fanconi syndrome and acute tubular damage. Glomerular lesions usually cause more severe proteinuria than tubulointerstitial lesions. Renal proteinuria may also be caused by inflammatory or infiltrative kidney disorders, such as pyelonephritis, leptospirosis, and neoplasia, which are often accompanied by an active urine sediment and ultrasound changes in the kidney.

Monitoring Renal Proteinuria

Transient renal proteinuria or albuminuria is probably of little consequence and does not need treatment. Persistent proteinuria or albuminuria with an inactive sediment, however, strongly suggests CKD. The ACVIM consensus statement defines persistent proteinuria or albuminuria as positive test results on three or more occasions, at least two weeks apart, while the IRIS guidelines base substaging on at least two urine samples collected over at least two weeks. Because persistent proteinuria can remain constant or increase or decrease over time, it should be monitored with quantitative methods to follow disease trends and the response to treatment.

Changes in proteinuria should always be interpreted in light of the patient's blood creatinine or SDMA, because proteinuria may decrease in progressive kidney disease as the number of functioning nephrons falls. Decreasing proteinuria with a stable blood creatinine or SDMA suggests improving kidney function, whereas decreasing proteinuria with an increasing creatinine or SDMA suggests progression of the disease.

Quantification of Proteinuria

If screening tests show persistent proteinuria, urine protein excretion should be quantified. This helps to assess the severity of the kidney lesions and the response to treatment or progression of the disease. Methods of quantifying proteinuria include the UPC and immunoassays for albuminuria, the latter expressed either as a urine albumin-to-creatinine ratio or in mg/dL of urine diluted to a standard specific gravity (for example, 1.010). An albumin concentration of 30 mg/dL or more in urine diluted to 1.010 will usually correspond to a UPC of 0.4 or more in cats and 0.5 or more in dogs.

The UPC and urine albumin-to-creatinine ratio from a single "spot" urine sample accurately reflect the amount of protein or albumin excreted in the urine over 24 hours (reference 28). Because 24-hour urine collection is difficult, spot sampling has greatly helped the recognition of proteinuric kidney diseases in veterinary medicine. Most studies have shown that normal urine protein excretion in dogs and cats is less than 10 mg/kg per 24 hours and that normal UPC values are below 0.2. A UPC of 0.2 to 0.5 in dogs, or 0.2 to 0.4 in cats, is considered borderline proteinuria (reference 1). Persistent proteinuria with a UPC above 0.4 in cats or above 0.5 in dogs, once pre-renal and post-renal proteinuria have been ruled out, is consistent with glomerular or tubulointerstitial CKD, whereas a UPC above 2.0 strongly suggests glomerular disease (reference 1). The definition of "normal" may continue to change with further research.

Interestingly, although the UPC was a specific test for canine and feline albuminuria when compared with the species-specific quantitative immunoassay, a UPC cut-off of 0.2 produced an unacceptable number of false negatives (reference 9). In cats with CKD, the single best test for detecting albuminuria was the UPC, with a value of 0.2 or more considered positive, and both negative and positive results provided useful information (reference 10).

Based on serial testing in dogs with X-linked hereditary nephropathy, the UPC must change by at least 35% at high values (near 12) and by 80% at low values (near 0.5) to show a significant difference between serial results. One measurement reliably estimated the UPC when values were below 4, but two or more measurements were needed when values were above 4 (reference 29).

Why Renal Proteinuria Matters

Proteinuria, along with other abnormalities, has been found after partial surgical removal of kidney tissue in dogs and cats. Glomerular capillary hypertension, enlarged glomeruli, and proteinuria have been documented in dogs with the remnant kidney model of kidney failure (reference 30). In cats with the remnant kidney model of CKD, increases in single-nephron glomerular filtration rate occur together with glomerular enlargement, increasing pressures within the glomeruli, hyperfiltration, mesangial matrix expansion, and borderline proteinuria (reference 31).

Of clinical importance is the association between proteinuria and poor outcomes in dogs and cats with naturally occurring CKD. In affected dogs, the relative risk of uremic crises and death was about three times greater in dogs with a UPC above 1.0 (25 dogs) than in dogs with a UPC below 1.0 (20 dogs). In this study, the risk of an adverse outcome was about 1.5 times greater for every 1-unit increase in UPC, and kidney function declined faster in dogs with a higher UPC (reference 2). Similarly, relatively mild proteinuria (a UPC above 0.4) appears to predict shorter survival in affected cats. Increasing proteinuria was associated with increasing serum creatinine and increasing systolic blood pressure, presumably related to glomerular hyperfiltration, and the UPC, age, and serum creatinine (but not blood pressure) were independently associated with death (reference 3). Shorter survival was also associated with an increased UPC as an independent risk factor in another study of cats with naturally occurring CKD (reference 5).

Even in patients without azotemia, the development of proteinuria has been linked with poor outcomes. The development of proteinuria was associated with an increased risk of death from all causes in cats that had normal kidney function when the proteinuria was first detected (reference 32). Proteinuria (the UPC before and after treatment, and the change in UPC) was also the only variable related to survival in 141 client-owned cats with naturally occurring systemic hypertension, in which amlodipine treatment reduced both blood pressure and proteinuria (reference 4). In addition, proteinuria was significantly associated with the development of azotemia in a prospective longitudinal study of 95 cats aged 9 years and older (median age 13 years) (reference 33). When these non-azotemic cats were followed for 12 months or until death or the development of azotemia, 29 of the 95 cats (30.5%) developed azotemia (serum creatinine above 2.0 mg/dL), which correlated with proteinuria (median UPC 0.19 in cats that became azotemic versus 0.14 in those that did not).

Finally, proteinuria has been associated with the progression of CKD in cats. In 59 cats with CKD (serum creatinine above 2.0 mg/dL, urine specific gravity below 1.035, and a history and clinical signs compatible with CKD rather than acute kidney injury), the UPC correlated with both the kidney interstitial fibrosis score and the maximum glomerular volume, and 34 of the 59 cats (58%) were classified as proteinuric (reference 34). In another study, cats with CKD that died within 1 month (16 cats) had a significantly higher UPC than those that survived longer than 1 month (34 cats). In the surviving group, the UPC was the only laboratory variable that changed consistently (increased) compared with the first visit, and it was the variable most likely to be associated with death (reference 35). In a third study, each 0.1-unit increase in UPC was associated with a 24% increase in the risk of CKD progression in client-owned cats, and when cats with stable CKD (112 cats) were compared with cats with progressive CKD (101 cats), the median UPC was higher in the progressive group (0.27 versus 0.14) (reference 36).

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