The presence of albumin in the urine in quantities greater than the reference limit, but below the limit of detection of standard urine dipstick assays, is defined as microalbuminuria. Microalbuminuria consistently precedes development of overt proteinuria in humans and is interpreted as a warning sign of glomerular disease.1–3 In addition, systemic inflammation is associated with protein leakage across endothelia and development of microalbuminuria, making microalbuminuria an excellent marker of underlying disease and a predictor of morbidity and mortality rates in humans with underlying or primary diseases.4–9 The benefits of early identification of at-risk patients have led to recommendations by some investigators10 to use microalbuminuria as a screening tool for nephritic disease in the general population.
Microalbuminuria can be measured via multiple techniques, including 24-hour urinary albumin excretion or the urinary albumin excretion rate, untimed single-sample urine albumin concentration, and standardization of 1-time albumin measurement by use of the UAC ratio. Two microalbuminuria assays (a semiquantitativea and a quantitativeb assay) have been validated for use in dogs. In both assays, albumin measurement is standardized by normalization of values to a urine specific gravity of 1.010. Advantages associated with the use of microalbuminuria testing over urine dipstick tests for protein and determination of the UPC ratio include higher sensitivity and specificity for detection of urinary protein and decreased influences of exercise, inflammation of the lower portion of the urinary tract, and hematuria on interpretation of results.11,b Results of preliminary investigation in cats suggest that semiquantitative microalbuminuria testing yields prognostic data equivalent to determination of the UAC ratio, whereas in humans, UAC ratio determination is considered more accurate for detecting microalbuminuria.f Interpretation of the UAC ratio in humans, however, can be complicated by differences in urine creatinine excretion between genders and among races.12,13 Because creatinine excretion is not affected by sex in dogs, the UAC ratio may have better predictive values than microalbuminuria measurement in dogs. To our knowledge, this hypothesis has not been tested.
In a recent studyg in which > 3,000 dogs owned by veterinary hospital personnel were evaluated, the prevalence of microalbuminuria in dogs increased with age. When follow-up data were obtained for 572 of the 751 dogs that were microalbuminuric, it was determined that 322 (56.3%) dogs had underlying infectious, inflammatory, neoplastic, or metabolic diseases that could be associated with alterations in glomerular permeability or secondary glomerular injury.14 An additional 177 (31%) of those dogs had renal disease, 69 (12.1%) had no specific diagnosis, and the remainder had either multiple diagnoses or a disease process not thought to be associated with proteinuria. The prevalence of systemic disease in dogs that were not microalbuminuric was not determined; therefore, the predictive value of those results is unknown.
In another study,h 105 dogs were evaluated by means of urinalysis, UPC ratio determination, and testing for microalbuminuria. Infectious, inflammatory, or neoplastic diseases that have been associated with proteinuria were diagnosed within 3 months of initial urine collection in 31 (56.3%) of the dogs that had positive results of a microalbuminuria assay but negative results of dipstick testing and 6 (26%) dogs that had negative results of both a microalbuminuria assay and dipstick test. Although the difference between groups was not significant, there was a high likelihood of type 2 error in that study as a result of the small study sample size. Data obtained by comparing clinical disease findings in dogs with and without microalbuminuria are needed to assess the diagnostic utility of the tests.
The objective of the present study was to evaluate semiquantitative and quantitative assays for microalbuminuria and determination of the UAC ratio in detection of systemic disease in dogs without overt proteinuria.
Materials and Methods
Patient selection—Six hundred dogs that were examined serially at the Colorado State University Veterinary Teaching Hospital from March 3, 2003, to August 20, 2003, and in which urine samples were collected were initially evaluated and prospectively enrolled in the study. Case numbers were recorded, and urine was frozen. After a period of 3 months, records were reviewed and data were extracted. Of the initial 600 dogs enrolled, results of a dipstick test for urine protein were negative and the medical record was complete in 408 dogs. Records were reviewed by 1 of 2 authors (JCW or VLG), and clinical diagnoses entered within 3 months of the time of urine collection were recorded. At the time of data collection, urinalysis results were not available to the investigators. Clinical diagnoses included healthy; neoplasia (excluding lipomas); infectious, immune-mediated, or inflammatory disease; urinary tract disease; and other. Rectal temperature, systolic blood pressure, diagnostic tests performed, and medications dogs were receiving were also recorded.
Urine assays—Urine samples collected by free catch, catheterization, or cystocentesis were included. Urinalysis was performed by technicians in the Clinical Pathology Laboratory at the veterinary teaching hospital, and samples were frozen at −20°C until the other assays were performed. Technicians unaware of the urinalysis results performed the MALBE according to the manufacturer's instructions. Briefly, the sample was normalized to a urine specific gravity of 1.010 by dilution with distilled water in a sample dilution tube. The test device was inserted into the diluted sample for a minimum of 3 minutes, and results were determined by comparing the intensity of 2 colored bands in the test window.
After the MALBE was performed, samples were refrozen for transport and submitted to a commercial laboratoryi where the MALBQ, urine total protein assay, and urine creatinine assay were performed by technicians unaware of the urinalysis results. The MALBQ is an immunoturbidimetric assay in which results are generated from quantitative measurement of agglutination caused by the reaction of polyclonal anti-albumin antibodies and albumin in the urine sample. Turbidity was measured at 340 nm and 700 nm on an analyzer. The albumin concentration in the sample was determined by comparing sample absorbance to a multipoint calibration curve, and results were normalized to a urine specific gravity of 1.010. Evaluation of earlier (unpublished) data indicated that trace quantities of albumin in canine urine samples did not degrade with repeated freeze-thaw cycles. The UPC and UAC ratios were calculated by dividing the total protein or albumin concentration by the creatinine concentration of each sample prior to standardization for specific gravity.
Statistical analysis—All MALBE and MALBQ results 3 1 mg/dL were considered positive. Cutoff UAC ratio values of 100 (UAC100) and 200 (UAC200) mg/g were evaluated; those values were chosen on the basis of human data and data obtained in cats.15 Cutoff values for the UPC ratio 3 0.1 (UPC0.1) and 3 0.5 (UPC0.5) were also evaluated.
Diagnostic sensitivity and specificity of the MALBQ and MALBE assays and for the UPC0.1, UPC0.5, UAC100, and UAC200 ratios were calculated via c2 analysis with presence or absence of systemic disease designated as the independent variable. Backward-selection logistic regression was performed to evaluate associations between disease status, sex, age, results of bacterial culture of urine, rectal temperature, pyuria, hematuria, bacteriuria, or the interaction between disease status and age, and results of MALBQ, MALBE, UPC0.1, and UPC0.5 tests. Disease status was designated as healthy or diseased and was included in the statistical analysis as a dichotomous explanatory variable. All other explanatory variables (eg, age, results of bacterial urine culture, rectal temperature, pyuria, hematuria, and bacteriuria) were included in the model as continuous explanatory variables. Dogs with disease were suballocated into various disease categories, and logistic regression was performed on those disease subpopulations. However, in a number of the subpopulations, the model-fitting procedure failed to converge, probably as a result of insufficient sample sizes. Results of subpopulation evaluations where model-fitting procedures converged were summarized. Values of P < 0.05 were considered significant. Odds ratios were determined where possible. Data were analyzed by use of a commercially available software package.j
Results
Of the 408 dogs included in analyses, 56 had > 1 disease. Of the remaining 352 dogs, 48 (14%) were classified as healthy; 81 (23%) had a diagnosis of neoplasia; 67 (19%) had infectious, immune-mediated, or inflammatory disease; 45 (13%) had urinary disorders; and 111 (32%) had other diseases. The distribution of values for microalbuminuria obtained via MALBQ was not the same among those categories (Figure 1). Eight urine samples were obtained by use of an indwelling urinary catheter, whereas the other samples were obtained by free catch or cystocentesis. The distribution of dogs with positive results of the MALBQ, MALBE, UPC0.1 ratio, UPC0.5 ratio, UAC100 ratio, and UAC200 ratio by diagnostic code was summarized (Table 1). The sensitivity and specificity of the MALBQ, MALBE, UPC0.1 ratio, UPC0.5 ratio, UAC100 ratio, and UAC200 ratio for distinguishing healthy from nonhealthy dogs were determined (Table 2). When results were calculated with and without dogs with multiple diagnoses, no significant differences were detected.
Distribution of MALBQ values for microalbuminuria by diagnosis category in 408 dogs with or without disease and with negative results of a dipstick test for urine protein. Healthy = Dogs that had no disease conditions. Disease = Dogs that were not categorized as healthy. Inf = Dogs with infectious, immune-mediated, or inflammatory disease. Mult = Dogs with > 1 diagnosis. Neop = Dogs with neoplastic disease. Other = Dogs with 1 disease that did not fall into one of the other primary disease categories. Urinary = Dogs with urinary tract disease. The dotted line represents the cutoff value of 1 mg/dL. The line in each box represents the median MALBQ value for that diagnosis category, the box encompasses the 25th to 75th percentiles, whiskers are the 10th and 90th percentiles, and individual dots represent outliers.
Citation: Journal of the American Veterinary Medical Association 229, 6; 10.2460/javma.229.6.958
Distribution of urine samples with positive results of MALBQ and MALBE and UPC and UAC ratios by clinical diagnosis and in all dogs as a group (n = 352) that were healthy or had a single disease and in which results of a dipstick test for urine protein were negative. Data are given as percentage (number) of dogs.
| Clinical diagnosis | MALBQ | MALBE | UPC0.1 | UPC0.5 | UAC100 | UAC200 | All dogs* |
|---|---|---|---|---|---|---|---|
| Healthy | 6 (7) | 4 (4) | 16 (39) | 0 (0) | 0 (0) | 0 (0) | 14 (48) |
| Neoplastic | 31 (34) | 30 (34) | 22 (54) | 38 (5) | 52 (15) | 45 (5) | 23 (81) |
| Infectious-immune-inflammatory | 20 (22) | 21 (24) | 18 (45) | 15 (2) | 21 (6) | 27 (3) | 19 (67) |
| Urinary system | 14 (16) | 13 (15) | 12 (29) | 15 (2) | 3 (1) | 0 (0) | 13 (45) |
| Other | 29 (32) | 32 (37) | 33 (84) | 31 (4) | 24 (7) | 27 (3) | 32 (111) |
| Total | 100 (111) | 100 (114) | 100 (251) | 100 (13) | 100 (29) | 100 (11) | 100 (352 |
All dogs with 1 diagnosis code by diagnosis category.
Sensitivity and specificity of urine tests for detection of systemic disease in 408 dogs with 1 disease, multiple diseases, or without disease and in which results of a dipstick test for urine protein were negative.
| Variable | MALBQ | MALBE | UPC0.1 | UPC0.5 | UAC100 | UAC200 |
|---|---|---|---|---|---|---|
| Sensitivity (%) | 35.6 | 36.9 | 71.1 | 4.5 | 10 | 3.6 |
| Specificity (%) | 85.4 | 91.7 | 18.8 | 100 | 100 | 100 |
See Table 1 for remainder of key.
Logistic regression could not be performed for UPC0.5, UAC100, or UAC200 ratio determination because of the low number of dogs with positive test results. Significant associations between older age, presence of disease, high BUN and serum creatinine concentrations, and hematuria and positive results of certain urine tests were detected (Table 3). There was no significant association between sex, blood pressure, bacterial urine culture results, rectal temperature, pyuria, or bacteriuria and results of MALBQ, MALBE, or the UPC0.1 ratio. The only disease subpopulations in which there were enough samples with positive results for logistic regression analysis were neoplasia, infectious-immune-inflammatory, urinary system, and other.
Results of logistic regression for associations between positive results of microalbuminuria assays or UPC0.1 ratio and disease status in dogs.
| MALBQ | MALBE | UPC0.1 | ||||
|---|---|---|---|---|---|---|
| Disease category | Pvalue | OR(CI) | Pvalue | OR(CI) | Pvalue | OR(CI) |
| Healthy (n = 48 dogs) or with 1 disease (304 dogs) Age | < 0.001* | 1.148(1.079–1.221) | < 0.001* | 1.129(1.061–1.200) | 0.047* | 1.065(1.001–1.133) |
| Health status (diseased vs healthy)† | 0.051 | 2.331(0.998–5.443) | 0.004* | 4.845(1.680–13.971) | 0.021* | 2.086(1.115–3.901) |
| BUN | 0.005* | 1.039(1.012–1.066) | < 0.001* | 1.049(1.021–1.078) | > 0.10 | — |
| Serum creatinine concentration | 0.056 | 0.595(0.350–1.013) | 0.029* | 0.550(0.322–0.941) | > 0.10 | — |
| Hematuria | 0.002* | 1.479(1.159–1.887) | 0.092 | 1.225(0.967–1.551) | 0.006* | 1.874(1.196–2.936) |
| Neoplasia (81 dogs) Having this disease subcategory | 0.046* | 2.690(1.017–7.113) | < 0.001* | 8.070(2.609–24.958) | 0.004* | 3.186(1.460–6.949) |
| Age | 0.047* | 1.148(1.002–1.315) | > 0.10 | — | > 0.10 | — |
| Hematuria | 0.082 | 1.413(0.957–2.087) | > 0.10 | — | > 0.10 | — |
| BUN | > 0.10 | — | 0.025* | 1.058(1.007–1.112) | > 0.10 | — |
| Serum creatinine concentration | > 0.10 | — | 0.095 | 0.391(0.130–1.179) | > 0.10 | — |
| Infectious-immuneinflammatory-mediated (67 dogs) Having this disease subcategory | > 0.10 | — | > 0.10 | — | 0.015* | 1.048(1.009–1.089) |
| Urinary systems (45 dogs) Having this disease subcategory | > 0.10 | — | > 0.10 | — | > 0.10 | — |
| Age | 0.078 | 1.143(0.985–1.327) | > 0.10 | — | > 0.10 | — |
| Urine bacterial culture | 0.009* | 2.717(1.278–5.779) | > 0.10 | — | > 0.10 | — |
| Hematuria | 0.074 | 1.814(0.945–3.483) | 0.018* | 2.230(1.145–4.343) | > 0.10 | — |
| BUN | > 0.10 | — | 0.018* | 1.062(1.010–1.117) | > 0.10 | — |
| Bacteruria | > 0.10 | — | < 0.001* | 2.497(1.499–4.161) | > 0.10 | — |
| Rectal temperature | > 0.10 | — | > 0.10 | — | 0.063 | 0.480(0.221–1.041) |
| Other (90 dogs) Having this disease subcategory | > 0.10 | — | 0.018* | 1.060(1.010–1.113) | 0.005* | 1.048(1.015–1.083) |
| Age | 0.001* | 1.221(1.083–1.377) | < 0.001* | 1.236(1.096–1.394) | > 0.10 | — |
| Serum creatinine concentration | 0.005* | 0.214(0.073–0.626) | 0.018* | 0.271(0.092–0.798) | 0.079 | 0.441(0.177–1.099) |
| Urine bacterial culture | > 0.10 | — | > 0.10 | — | 0.018* | 0.209(0.058–0.761) |
Significant (P, 0.05) value.
Compared with a health status of healthy.
OR = Odds ratio. CI = Confidence interval. – = Not calculable because of the lack of significance.
See Tables 1 and 2 for remainder of key.
Discussion
The etiologies of proteinuria may be classified as prerenal, functional renal, pathologic tubular, or pathologic glomerular.16 Overt proteinuria (ie, UPC ratio > 1.0) is commonly accepted as abnormal and is an indication for further diagnostic testing. The clinical importance of low-grade proteinuria remains unknown. Data from dogs, cats, and humans suggest that the finding of microalbuminuria may be an indication for further evaluation because it may be associated with higher morbidity and all-cause mortality rates.4–10,17,k,l The development of a quantitative assay for accurate measurement of microalbuminuria has been pivotal to this discovery in human medicine.
There are 2 major clinical uses for results of microalbuminuria assays. Because the assays are more specific than dipstick assays for urine protein loss, they can be used to confirm positive dipstick test results. Because microalbuminuria assays are more sensitive than the dipstick and UPC tests, they can be used to detect urine protein loss below the limits of detection of urine dipsticks. Increased urine albumin concentrations have been reported in dogs with neoplasia, but not in those with orthopedic disease.m To the authors' knowledge, there are no published studies in which an association was detected between microalbuminuria and systemic disease in dogs without overt proteinuria. The best combinations of sensitivity and specificity for disease were observed with the MALBE and the MALBQ tests. Exclusion of samples with positive results of a dipstick test for urine protein from this study likely resulted in decreased values for sensitivity and specificity of the microalbuminuria tests, compared with results of previous analyses. Given their low specificity and sensitivity, respectively, both the UPC0.1 and UPC0.5 ratios appeared to have limited value for screening dogs without overt proteinuria for systemic disease. These findings should also be considered in assessment of results of the UPC ratio with a positive cutoff value of 1.0.
The poor diagnostic usefulness of UAC100 and UAC200 ratios for screening dogs for systemic disease was unexpected. In humans, significant associations exist between the UAC ratio and idiopathic hypertension3 and diabetic nephropathy18–20; determination of the UAC ratio has also been more accurate than microalbuminuria assay results in some studies.12,13 In a previous investigation15 in cats, there was a significant association between the UAC ratio and both hypertension and azotemia. The UAC ratio is a predictor of death in healthy cats as well as in cats with those conditions.15,l Similar results would be anticipated in dogs, but this was not supported in the present study. The UAC100 and UAC200 ratios had poor sensitivity in the present study and thus appeared to be of little use for detection of occult systemic disease in dogs with negative results of dipstick tests for urine protein. Further studies are recommended before the diagnostic usefulness of the UAC100 and UAC200 ratios is completely discounted. However, the results of the present study suggest that if dogs with negative dipstick test results are to be further assessed, the MALBE or MALBQ should be used.
The association between low levels of proteinuria and increasing age in dogs of this study supports results of a previous study.g To our knowledge, persistence of this association, independent of disease status, has not been previously reported and contrasts with findings from previous reports15,21 in cats. The association between low-grade proteinuria and disease as indicated by the MALBE was striking. The association between azotemia and MALB supports the use of microalbuminuria testing for early identification of dogs with renal disease. However, the lack of association between the urinary tract disease category and microalbuminuria appears to conflict with the results. We feel that this was not an unexpected finding because that diagnosis category included dogs with any urinary tract problem, including inappropriate elimination or urinary incontinence, whereas values for BUN and serum creatinine concentration better reflect the subset of dogs with true renal disease.
The association between neoplasia and positive results of microalbuminuria testing is of potential clinical importance because occult neoplasia can be difficult to diagnose and is not typically identified on routine health screening tests such as hemograms and serum biochemical analyses. Identification of late-stage neoplasia in an apparently healthy animal is a common source of frustration for clients and practitioners. Should testing for microalbuminuria prove to be a means of identifying animals with an increased likelihood of occult neoplastic disease, it may be a useful adjunct to other screening tests in geriatric veterinary patients. Many of the dogs in the “other” disease subcategory had systemic diseases that were likely inflammatory in nature, but the dogs had not been evaluated extensively enough to be grouped in a given subcategory (eg, liver disease). Therefore, the association between that disease subcategory and MALBE results was not surprising.
The present study had a number of limitations. To prevent bias or operator variability, samples were analyzed en masse. This approach helped to limit diagnostic work-up bias because urine test results were not available to the dogs' attending clinicians. The downside of this approach was that clinicians did not have the opportunity to use urine test results in assessment of their patients. Because the study was observational, another important limitation was that some of the dogs enrolled were undergoing ongoing management during the time of the study. Some of those dogs were in remission for incurable disease, and some were almost recovered from previously diagnosed disease, a fact that may limit applicability of these results to a naïve population. Given the high prevalence and the continuum of disease in geriatric dogs, we believe that this concern is of limited importance. The nonrandomized enrollment of dogs at the teaching hospital and the disease characteristics of dogs examined at a tertiary care facility resulted in a disparity between the number of healthy and unhealthy animals. This distribution inequality may have skewed interpretation of the statistical analyses because the number of dogs with positive results was not similar to the number of dogs with negative results. Finally, the inclusion of dogs with diseases not known to be associated with proteinuria (eg, dermatologic disease) in the disease category for logistic regression analysis may have biased the analysis against identifying significant correlations. Such dogs were included because other options (eg, censoring those cases or categorizing them as healthy) would have decreased applicability of the study results to the general practice population. In addition, such choices would have required prospective judgment of which diseases should or should not be associated with microalbuminuria without the benefit of objective supporting data.
Results of this study support the recommendation to evaluate geriatric animals for occult proteinuria even when the results of urine dipstick testing are negative.16 Point-of-care tests are used frequently in veterinary practices. In the present study, sensitivity and specificity of the MALBE for detection of systemic disease were superior to those of the other tests, and the MALBE can be performed in the veterinary clinic. We conclude that there is benefit for the use of the MALBE or MALBQ in conjunction with other routine geriatric screening tests (eg, signalment, history, physical examination, CBC, serum biochemical analysis, urinalysis, and blood pressure) to increase the likelihood of identifying occult disease. A prospective study in which the positive and negative predictive values of other geriatric screening tests are evaluated with and without a microalbuminuria assay is needed to further validate this recommendation.
ABBREVIATIONS
| UAC | Urine albumin-creatinine |
| UPC | Urine protein-creatinine |
| MALBE | Microalbuminuria assay (semiquantitative) |
| MALBQ | Microalbuminuria assay (quantitative) |
ERD-HealthScreen Canine Urine Test, Heska Corp, Loveland, Colo.
ERD Test, Heska Corp, Loveland, Colo.
Jensen WA, Andrews J, Simpson D. Prevalence of microalbuminuria in dogs (abstr). J Vet Intern Med 2001;15:300.
Grauer GF, Moore LE, Smith AR, et al. Comparison of conventional urine protein test strip method and a quantitative ELISA for the detection of canine and feline albuminuria (abstr). J Vet Intern Med 2004;18:127.
Gary AT, Cohn LA, Kerl ME, et al. The effects of exercise on microalbuminuria in dogs (abstr). J Vet Intern Med 2003;17:229.
Syme HM, Elliott J. Comparison of urinary albumin excretion normalized by creatinine concentration or urine specific gravity (abstr). J Vet Intern Med 2005;19:240.
Radecki S, Donnelly R, Jensen WA, et al. Effect of age and breed on the prevalence of microalbuminuria in dogs (abstr). J Vet Intern Med 2003;17:110.
Whittemore JC, Jensen WA, Prause L, et al. Comparison of microalbuminuria, urine protein dipstick, and urine protein creatinine ratio results in clinically ill dogs (abstr). J Vet Intern Med 2003;17:234.
HESKA Veterinary Diagnostic Laboratory, Loveland, Colo.
Statview for Windows, version 5.0.1, SAS Institute Inc, Cary, NC.
Turman CA, Vaden SL, Harris TL, et al. The prevalence of microalbuminuria in dogs and cats in an intensive care unit (abstr). J Vet Intern Med 2004;18:124.
Walker D, Syme HM, Markwell P, et al. Predictors of survival in healthy, non-azotaemic cats (abstr). J Vet Intern Med 2004;18:123.
Pressler BM, Proulx DA, Williams LE, et al. Urine albumin concentration is increased in dogs with lymphoma or osteosarcoma (abstr). J Vet Intern Med 2003;17:101.
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