Implications for Management

Chapter 187


Implications for Management

Proteinuria is a general term that is used to describe the presence of excessive amounts of any type of protein in the urine. In most dogs and cats, in both health and disease, albumin is the primary urine protein. Proteinuria/albuminuria can arise from numerous causes (e.g., physiologic or benign; prerenal, renal, or postrenal). Therefore, when proteinuria is detected, localization of its source is a primary diagnostic objective. When renal proteinuria/albuminuria is suspected, the next diagnostic objectives are longitudinal monitoring and documentation of persistence followed by quantitation of the magnitude of proteinuria/albuminuria.

Proteinuria/albuminuria long has been established as a marker of kidney disease in dogs, but not long ago it was viewed to be primarily a marker of canine glomerular disease and likely not significant unless the urine protein/creatinine ratio was higher than 3.0 or it was associated with hypoalbuminemia. Today we recognize that proteinuria/albuminuria often is associated with chronic kidney disease (CKD) in both dogs and cats and that it can arise from both glomerular and tubular lesions. We also have recognized that even low-level proteinuria/albuminuria is a risk factor for CKD progression in both dogs and cats. For these reasons, detection, monitoring, and treatment of dogs and cats with renal proteinuria/albuminuria have received renewed interest.

Detection of Proteinuria

The dipstick colorimetric test is the most common screening test for proteinuria. This test is inexpensive, easy to use, and primarily measures albumin. However, sensitivity and specificity for albuminuria are relatively low with this method. False-negative results (decreased sensitivity) may occur with Bence Jones proteinuria, low urine concentrations of albumin, or dilute or acidic urine. The lower limit of detection for the conventional dipstick test is approximately 30 mg/dl. False-positive results also are common in both cats and dogs with dipstick testing but occur more frequently in cats. For example, when 599 canine and 347 feline urine samples were analyzed by both a conventional urine protein test strip method (Multistix Reagent Strips or Roche Chemstrip 9) and a canine or feline albumin-specific quantitative enzyme-linked immunosorbent assay (ELISA) (see later) there were disparate results. The sensitivity of conventional urine protein dipsticks for albuminuria in canine and feline urine (a trace positive reaction or greater) was 81% and 90%, respectively, but the specificity was only 48% and 11%, respectively (Lyon et al, 2010).

The sulfosalicylic acid (SSA) precipitation test is performed by mixing equal quantities of urine supernatant and 3% to 5% SSA in a glass test tube and grading the turbidity resulting from precipitation of protein on a 0 to 4+ scale. In addition to albumin, the SSA test can detect globulins and Bence Jones proteins to a greater extent than the dipstick test. False-positive results may occur if the urine contains radiographic contrast agents, penicillin, cephalosporins, sulfisoxazole, or thymol (a urine preservative), and for unknown reasons. The protein content also may be overestimated with the SSA test if uncentrifuged, turbid urine is analyzed. The reported sensitivity of the SSA test is approximately 5 mg/dl. Because of the relatively poor specificity of conventional dipstick analysis, many reference laboratories confirm a positive dipstick test result for proteinuria using the SSA test. The sensitivity of the SSA test for albuminuria in canine and feline urine (a trace positive reaction or greater) was found to be 73% and 58%, respectively, but the specificity was only 64% and 25%, respectively (Lyon et al, 2010).

Based on the study of canine urine mentioned earlier, if the urine dipstick or SSA result is 2+ or higher there is a high probability that the sample is positive for albumin. However, if the dipstick result is trace or 1+ positive, a turbidimetric SSA analysis should be performed to confirm the diagnosis of proteinuria. When both tests are performed simultaneously they should be interpreted in series to increase specificity (results of both tests should be positive for the sample to be considered positive for albuminuria), rather than in parallel fashion. If dipstick and SSA results both fall into the trace to 1+ range, positive results for albuminuria should be confirmed with a more specific assay such as the ELISA-based test.

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-positive results. 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%, which indicates that neither test provided useful information regarding albuminuria. Based on these data, urine albumin detection in the feline patient always should be performed with a higher-quality assay such as the species-specific ELISA. In cats with chronic kidney disease, the accuracy of the dipstick and SSA tests improves in comparison with the feline-specific albuminuria assay (Hanzlicek et al, 2012), presumably due to a higher magnitude or a higher percentage of albumin in the urine.

Proteinuria detected by these semiquantitative screening methods historically has been interpreted in light of the urine specific gravity and urine sediment. For example, a positive dipstick reading of trace or 1+ proteinuria in hypersthenuric urine often has been attributed to urine concentration rather than abnormal proteinuria. In addition, a positive dipstick reading for protein in the presence of hematuria or pyuria often has been attributed to urinary tract hemorrhage or inflammation. Although both variables must be taken into consideration, the conventional interpretation may not be correct. Given the limits of sensitivity of the conventional dipstick test, any positive result for protein, regardless of urine concentration, may indicate an abnormality (except in the case of false-positive results). Likewise, hematuria and pyuria have an inconsistent effect on urine protein/albumin concentrations; not all dogs with hematuria and pyuria have albuminuria. In patients with gross hematuria or microscopic pyuria, the source of the hemorrhage or inflammation should be diagnosed and treated before further assessment of the proteinuria/albuminuria.

Detection of Albuminuria

Albuminuria can be measured by point-of-care semiquantitative tests (e.g., the Heska E.R.D.-HealthScreen urine test) and quantitative immunoassays at reference laboratories. These tests are both sensitive and specific for canine and feline albumin. Microalbuminuria is defined as concentrations of albumin in the urine that are higher than normal (>1.0 mg/dl) but below the limit of detection using conventional urine dipstick tests (<30 mg/dl). Urine albumin concentrations can be adjusted for differences in urine concentration by dividing by urine creatinine concentrations. Alternatively, and more commonly, urine can be diluted to a standard specific gravity (1.010) before assay.

The use of microalbuminuria tests is indicated in the following circumstances:

1. When conventional screening tests for proteinuria produce equivocal or conflicting results or false-positive results are suspected.

2. When conventional screening tests for proteinuria give negative results in apparently healthy older dogs and cats and a more sensitive screening test is desired.

3. When conventional screening tests for proteinuria give negative results in apparently healthy young dogs and cats with a familial risk for developing proteinuric renal disease and a more sensitive screening test is desired.

4. When conventional screening tests for proteinuria give negative results in dogs and cats with chronic illnesses that are associated with proteinuric renal disease and a more sensitive screening test is desired.

5. Follow-up after a positive result on a previous microalbuminuria test to document persistence of the albuminuria.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Implications for Management
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