Simplified Screening for Microalbuminuria

Methods

We tested 221 urine specimens obtained from the outpatient laboratory of a general hospital. The specimens had been randomly collected from primary care clinics and from a diabetes clinic that routinely sends urine specimens for all patients to the laboratory. Specimens from a renal clinic were not eligible for the study. Most specimens were early-morning samples with a specific gravity greater than 1015 in 168. Albumin in all samples was measured by radioimmunoassay done using ¹²⁵I-labeled crystalline human albumin and antihuman albumin, as described elsewhere [10]. Three screening tests were evaluated.

The Micral-Test immunoassay (Boehringer Mannheim, Mannheim, Germany) is based on the color shift of a monoclonal antibody (IgG) to human albumin labeled with colloidal gold, a shift that occurs after IgG binds with urinary albumin. The results of this assay were read in a semiquantitative manner as 0 mg/L, 20 mg/L, 50 mg/L, or 100 mg/L. A reading of 0 mg/L was interpreted as negative, and a reading of 20 mg/L or more was considered positive, according to the manufacturer's recommendations.

In the urine protein precipitation test with sulfosalicylic acid, five drops of 20% sulfosalicylic acid were added to 3 mL of urine in one test tube; that tube was compared with a tube of untreated urine held against a dark background. Tubes were observed immediately after the addition of sulfosalicylic acid, and turbidity was taken to indicate proteinuria.

Chemically impregnated dipsticks (Chemstrips, Boehringer Mannheim) were used according to the manufacturer's instructions. Results were recorded as negative, trace, or 1+ positive.

The results were analyzed by using Microsoft Excel software (Microsoft Corp., Redmond, Washington), and statistical measures were calculated in the standard manner.

Results

We used an upper limit of normal of less than 20 mg/L for the urinary albumin concentration [11]. In a concentrated urine sample, this corresponds roughly to an albumin excretion rate of 30 mg/d [12]. Our results, shown in the Table 1, indicate that a negative Micral-Test reading had a negative predictive value of 99%, a negative sulfosalicylic acid test result had a negative predictive value of 95%, and a negative result on Chemstrips had a negative predictive value of 96%. Seventy-four urine specimens tested negative on both sulfosalicylic acid testing and Chemstrips; on radioimmunoassay, 73 of these specimens were confirmed to be negative. Thus, the combination of a negative sulfosalicylic acid test result and a negative result on Chemstrips virtually ruled out microalbuminuria.

However, all three screening tests yielded high rates of false-positive results on a single testing. The positive predictive values were 21% with Micral-Test, 33% with sulfosalicylic acid testing, 19% with Chemstrips, and 34% with the combination of Chemstrips and sulfosalicylic acid testing. This indicates the need to repeatedly test specimens that have positive results and proceed to radioimmunoassay if necessary.

Discussion

Because urinary albumin excretion varies from day to day in the same person [13], repeated testing is often necessary. Timed collections [12], measurement of albumin-to-creatinine ratios [14], and even measurement of albumin concentrations in early-morning urine specimens [15] are either too cumbersome or too expensive to use, especially in the large numbers of patients who need to be screened. Indeed, some investigators have done extensive cost–benefit analyses to determine whether testing for microalbuminuria is worthwhile [7, 16]. In our study of largely concentrated urine specimens, we took an albumin concentration of 20 mg/L as the upper limit of normal and found high negative predictive values, especially for tests used in combination. A Micral-Test reading of 0 mg/L had a very high negative predictive value, but readings of 20 and 50 mg/L were often false-positive readings. For screening, moreover, the use of Micral-Test strips alone would be expensive ($2 per strip in the United States), especially because false-positive results are frequent and necessitate repeated testing. Chemstrips cost approximately $0.40 apiece, and sulfosalicylic acid tests cost less than $0.10 each. All three testing methods take about 3 minutes each to perform. Assuming that a technician is paid $20 per hour, this amounts to $1 per test. Thus, the approximate costs of Micral-Test and the combination of Chemstrips and sulfosalicylic acid testing are $3 and $1.50, respectively.

Sulfosalicylic acid testing was previously found to be sensitive to a protein concentration of 20 to 100 mg/L [17]. It also had a very high negative predictive value (95%), so that a negative result on this test alone rules out most cases of microalbuminuria. We were also surprised by the excellent negative predictive value of Chemstrips, particularly because they have not been advocated for screening for microalbuminuria [18]. In fact, some investigators have used negative results on Chemstrips testing to select patients for studies of microalbuminuria [19]. In our study, a negative result on Chemstrips virtually ruled out microalbuminuria. Anecdotally, we observed that many physicians had difficulty interpreting a “trace” as positive because they had difficulty distinguishing its green color from that of a 1+ positive test result. We further found that combining sulfosalicylic acid testing and Chemstrips was particularly informative; negative results on both tests almost excluded microalbuminuria. Such combination testing is also consonant with the old teaching that testing for albuminuria or proteinuria should be done by two different methods, each confirming the other and thereby eliminating spurious results [17].

In our study, the prevalence of proteinuria was high because the specimens were obtained from primary care clinics and a diabetes clinic. Predictive values clearly depend on the population being tested: A negative predictive value in our set of specimens constitutes a more rigorous evaluation of the test than if the test were to be performed in specimens from a normal population. Unfortunately, we were unable to compare test performance in diabetic and nondiabetic patients.

Our findings have considerable economic implications because hundreds of thousands of patients with diabetes and perhaps other diseases, such as essential hypertension and AIDS, need to be tested. Although we do not rule out a role for the Micral-Test strips, we wish to emphasize that Chemstrips and sulfosalicylic acid testing are inexpensive. A negative result on both tests rules out microalbuminuria, and the tests can be repeated as necessary. In the laboratory, the tests can be done quickly and inexpensively and can even be automated. In the office, the tests can be easily done by the physician, an activity that would be consonant with the traditional view that urinalysis is part of the physical examination. Unfortunately, many hospitals in the United States have removed urinalysis equipment from their wards and clinics. Our data suggest a potential reason for maintaining the ability to examine urine at the bedside.

Dr. Arruda: Section of Nephrology, University of Illinois at Chicago, 820 South Wood Street, M/C 793, Chicago, IL 60612.