proteinuria

Proteinuria in dogs and cats

C. J. van der Meiden, MA
Veterinary clinic Van der Meiden, Nijverdal
Primary Veterinary Blood Bank Nederland, Nijverdal

The permeability of the glomerular capillary is such that proteins with a molecular weight greater than 60,000 Daltons (D) do not pass through. This also applies to albumin which is the smallest blood protein at a molecular weight of 69,000 D. Protein molecules that do pass through the glomerular capillary wall are reabsorbed by the (renal) tubular epithelium. The result is that only a very small quantity of protein is encountered in the urine of healthy dogs and cats. If the glomerulus is damaged, as in glomerulonephritis and amyloidosis, larger quantities of protein are able to pass through. Proteinuria results when the quantity of protein passing through is greater than the tubular resorption capacity. For this reason, proteinuria is seen as a significant diagnostic indicator of a kidney affliction.

Extra-renal causes for proteinuria are urinary tract infections where protein is added to the urine with infectious products and hemorrhage. Therefore, proteinuria must always be interpreted in conjunction with the results of the urine sediment examination.

Proteinuria is usually determined using the “dipstick method”. This method suffices as long as the clinician remembers the result can be a false positive if the urine is alkaline (pH > 7.5) or significantly concentrated. In addition, urine specific gravity must be taken into account when estimating the degree of protein loss. A 3 + result by dipstick on a sample with a specific gravity of 1.006 indicates far greater protein loss than the same result in a sample with a specific gravity of 1.035.

The UPC ratio
When quantifying urine protein loss, the specific gravity must be taken into account. The UPC ratio uses the quantity of urine creatinine to correct for the variation in the specific gravity. Since the individual excretion of creatinine is relatively constant, and there is little resorption in the tubuli, the UPC ratio can be utilized to determine the progress of the proteinuria.

A urine sample can be sent to a laboratory for the determination of the UPC ratio; the quantity of protein and creatinine in the sample will be determined. Research has demonstrated that creatinine determination using in-hospital equipment (including the Vettest 8008 and Reflovet) is unreliable if a number of analyzers are utilized.

When interpreting the UPC ratio, keep in mind that renal protein is not measured as with a urinary tract infection. The evaluation of a urine sedimentation rate can identify whether the proteinuria has a renal or an extra-renal origin.

Microalbuminuria
Microalbuminuria is defined as the presence of an abnormal quantity of albumin in urine but is under the detectable limit of most tests (for proteinuria), including the dipstick. Microalbuminuria is generally caused by changes in the permeability of the glomerular membrane; in addition, functional interruptions in the tubular function can also play a role. In humans it has been shown that microalbuminuria is a good parameter in documenting early kidney damage, especially in patients with diabetes mellitus and hypertension. In veterinary medicine the microalbuminuria test offers the potential to find patients with kidney problems while still in the early stages. By starting these patients on a treatment at an early stage, the subsequent creation of additional irreversible damage can be halted or delayed.

The most reliable method for demonstrating microalbuminuria is to collect a 24 hour urine sample and determining the quantity of albumin. Although reliable this method is expensive and difficult to perform in dogs and cats. The Bayer Clinitek®, a human, semi-quantitative test for microalbuminuria, determines the quantity of creatinine which aids in the correction of the specific gravity. A study performed in 2001 showed this test is unreliable in dogs (2).

The E.R.D. HealthScreen
The E.R.D.-Healthscreen® (Heska Corporation, Loveland, CO), a rapid immunological test for identifying microalbuminuria, uses monoclonal antibodies specifically targeted against feline or canine albumin. After the urine specific gravity is determined 1 milliliter of sample is transferred to an accompanying dilution tube. The tube is subsequently filled with distilled water, up to a line designating the specific gravity of the urine sample. This will standardize the sample with respect to specific gravity. The test strip is then placed in the tube for a minimum of three minutes after which the result can be read.

By comparing the color intensity of the blue bands in the testing device against the colors on a test chart, the quantity of albumin can be read off semi-quantitatively. A recent study showed the E.R.D.-Healthscreen® correlates well with other semi-quantitative methods for detecting proteinuria, including the UPC ratio (7).

Causes of microalbuminuria
A positive microalbuminuria test is to be considered as deviating, and indicates glomerular, tubular, or vascular injury of the kidney. This damage can be temporary or the beginning of chronic, progressive kidney disease. A transitory microalbuminuria can occur in dogs as a result of fever or significant physical exertion (4). If a test is positive it is important to determine if the microalbuminuria is persistent or is a temporary increase. Glomerular or tubular injury that leads to microalbuminuria does not have to indicate primary kidney disease. In many dogs the renal lesions that lead to persistent microalbuminuria are caused by disease processes elsewhere in the body. This could explain why the percentage of animals positive for microalbuminuria increases with age (6). Many abnormalities, including inflammation, infection and metabolic disease can lead to microalbuminuria. In a large study including 4031 dogs of employees of veterinary clinics, the prevalence of microalbuminuria, as determined using the E.R.D.-Healthscreen ®, was 4% in dogs under one year old, while 55% of the animals over the age of 15 years showed a positive microalbuminuria test (5). A follow-up study in 572 of the positive animals showed an underlying disease process in 56%. Table 1 gives an overview of the disease processes encountered.

Disease categories in animals with a positive microalbuminuria test (E.R.D. ®)
Abnormality	Number of dogs	percentage
Inflammation	113	19.8
Infection	104	18.2
Neoplasia	41	7.2
Metabolic abnormality	28	4.9
Multiple afflictions	36	6.3
Total	322	56.3

There was inflammation or infection in almost 40 percent (19.8 and 18.2) of the dogs. This is not surprising, since antigen-antibody complexes can be formed in both afflictions, and it is known that these immune complexes can be responsible for glomerular damage (immune complex nephritis)

Recommendations for the use of the E.R.D. Health Screen ® in actual practice
The E.R.D. Health-screen is able to show very slight quantities of albumin (1mg/dL) in urine. For this reason it is a significant diagnostic tool for searching out dogs and cats with the start of kidney damage. Animals that belong to a risk group for attaining a chronic kidney affliction as a result of age or genetic predisposition could be screened annually using the E.R.D. Health-screen ®. However, there are numerous afflictions that could cause temporary microalbuminuria, it should not be immediately concluded that a positive test is caused by a primary kidney affliction. Because microalbuminuria is sometimes only temporary, animals with a positive test should be tested again after several weeks. If it appears that the microalbuminuria is persistent, there is reason to further investigate an underlying systemic or renal affliction.

1. Trumel C, Diquélou A, Lefebvre H, Braun JP. Inaccuracy of routine creatinine measurement in canine urine. Vet Clin Pathol. 2004;33(3):128-32.
2. B.M. Pressler, S.L. Vaden, W. Jensen, D. Simpson. Detection of Canine Microalbuminuria Using Semi-Quantitative Test Strips Designed for use in Human Urine. American College of Veterinary Internal Medicine 19th Annual Meeting, Denver, CO, May 30-June 1, 2001.
3. Whittemore JC, Gill VL, Jensen WA, Radecki SV, Lappin MR. Evaluation of the association between microalbuminuria and the urine albumin-creatinine ratio and systemic disease in dogs. J Am Vet Med Assoc 2006 Sep 15; 229(6): 958-63.
4. Cary A, Cohn L, Kerl M, and Jensen W: The effects of exercise on urinary albumin excretion in dogs. J Vet Intern Med 18:52-55, 2004.
5. Cook A.K. et al. J Am Anim Hosp Assoc 32:313 – 322.
6. Radecki S, Donnelly R, Jensen WA and Stinchcomb DT (2003) Effect of age and breed on the prevalence of microalbuminuria in dogs. Journal of Veterinary Internal Medicine 17, 4067.
7. Garner BC, Wiedmeyer CE. Comparison of a semiquantitative point-of-care assay for the detection of canine microalbuminuria with routine semiquantitative methods for proteinuria. Vet Clin Pathol. 2007 Sep;36(3): 240-4.

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reprinted with kind permission from Gillian Harris
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