August 2001 · Vol. 50, No. 8
Screening for Microalbuminuria to Prevent Nephropathy in Patients with Diabetes: A Systematic Review of the EvidenceKathryn E.H. Reilly, MD, MPH
Submitted, revised, April 16, 2001.
From the Department of Family and Preventive Medicine, University of Oklahoma Health Sciences Center. Reprint requests should be addressed to Laine H. McCarthy, 900 NE 10th Street, Oklahoma City, OK 73104. E-mail: email@example.com.
OBJECTIVE: Our goal was to evaluate whether screening patients with diabetes for microalbuminuria (MA) is effective according to the criteria developed by Frame and Carlson and those of the US Preventive Services Task Force.
STUDY DESIGN: We searched the MEDLINE database (1966-present) and bibliographies of relevant articles.
OUTCOMES MEASURED: We evaluated the impact of MA screening using published criteria for periodic health screening tests. The effect of the correlation between repeated tests on the accuracy of a currently recommended testing strategy was analyzed.
RESULTS: Quantitative tests have reported sensitivities from 56% to 100% and specificities from 81% to 98%. Semiquantitative tests for MA have reported sensitivities from 51% to 100% and specificities from 21% to 100%. First morning, morning, or random urine sampling appear feasible. Assuming an individual test sensitivity of 90%, a specificity of 90%, and a 10% prevalence of MA, the correlation between tests would have to be lower than 0.1 to achieve a positive predictive value for repeated testing of 75%.
CONCLUSIONS: Screening for MA meets only 4 of 6 Frame and Carlson criteria for evaluating screening tests. The recommended strategies to overcome diagnostic uncertainty by using repeated testing are based on expert opinion, are difficult to follow in primary care settings, do not improve diagnostic accuracy sufficiently, and have not been tested in a controlled trial. Although not advocated by the American Diabetes Association, semiquantitative MA screening tests using random urine sampling have acceptable accuracy but may not be reliable in all settings.
preventive health medicine;
screening [non-MESH]. (J Fam Pract 2001; 50:661-668)
Six major reviews of the natural history, prevention, and treatment of diabetic nephropathy have been published.1-6 Key points of these overviews with regard to screening are that persistent microalbuminuria (MA) is a reliable marker for the presence of diabetic nephropathy in both patients with type 1 (insulin-dependent) and type 2 (non–insulin-dependent) diabetes mellitus, and that angiotensin-converting enzyme inhibitors (ACEIs) slow or prevent the progression of diabetic nephropathy in patients with MA. The latter benefit occurs in both patients with type 1 and type 2 diabetes and appears to be long-lasting.
At least 6 sets of recommendations7-13 that advocate routine MA screening in all patients with diabetes have been issued by various physicians’ groups and organizations. Current American Diabetes Association (ADA) guidelines permit 3 types of collection to measure urinary albumin excretion (UAE): 24-hour (<30 mg/24 hrs), timed (<20 mg/minute), and untimed random albumin/creatinine ratio (UACR, <30 mg/mg creatine),*Table 1w7,8 Dipstick semiquantitative rapid tests are included in the ADA guidelines as alternatives if quantitative assays are not readily available, but they must be confirmed by quantitative methods. Others have suggested that semiquantitative tests should not be considered substitutes for the other methods.4 The variability of UAE is considered too high to use urine albumin concentration (UAC) alone. The average intraindividual daily UAE variation is approximately 40%; standing, exercise, illness, and diuresis all increase UAE.14 Because of this variation, the ADA guidelines recommend that 2 of 3 tests (performed over a 3- to 6-month period) should provide elevated results before the patient is considered to have MA.7,8
Recommended strategies to overcome diagnostic uncertainty by repeated testing are difficult to follow in primary care settings and do not appear to improve diagnostic accuracy. Published recommendations are based on expert opinion regarding the performance of MA tests. However, no controlled trial of the effectiveness of MA screening has been reported.3 Although concern about diagnostic uncertainty has led to recommendations for repeated testing and the use of timed quantitative MA tests, these strategies may be difficult to follow in primary care settings and may not improve accuracy. With this systematic review we critically examined components of previous recommendations and addressed the question of whether persons with diabetes should be screened for MA.
We searched the MEDLINE database from 1966 to the present looking for studies describing diagnostic tests for MA. The search strategy included the medical subject headings “albuminuria” and “diabetes mellitus” and the text words “microalbuminuria,” “nephropathy or nephropathies,” and “screening or testing or diagnosis.” The reference lists of relevant articles and the 6 major review articles1-6 were searched by hand to locate additional pertinent articles. A second search following identical procedures was performed substituting “cost-benefit analysis” for “screening or testing or diagnosis.” Screening articles were included if: (1) the subjects were only patients with diabetes, (2) the studies investigated the use of untimed urine samples (first morning [FAM], morning [AM], random urine sampling [RUS]), (3) tests were performed only in an ambulatory setting, and (4) test performance (sensitivity and specificity) could be determined from the article. Though it was not recommended in the ADA guidelines, we included semiquantitative tests as possible alternatives, because these tests are in clinical use and have been extensively studied. We initially included articles if any 1 of the 4 reviewers thought they met the inclusion criteria. Articles considered relevant by 3 of the 4 reviewers were included in the final round. Only English language articles reporting studies in human beings were selected. We did not seek unpublished data.
The quality of the screening articles was graded by a consensus of 2 reviewers using published criteria.15 Studies that presented sufficient information were examined to determine if the test characteristics could be pooled to give summary point estimates.16 We attempted to combine sensitivities and specificities reported for: (1) quantitative tests with a cutoff UAC of 20 mg per L or greater, (2) the same semiquantitative test used with any type of urine sample, or (3) the same semiquantitative test used with 1 type of urine sample. Using the chi-square test, we tested homogeneity among the sensitivities and specificities reported in the each of the studies. Studies were considered homogeneous if P was .05 or greater. Confidence intervals were calculated using the normal approximation to the binomial method.17
MA screening recommendations were analyzed using the criteria of Frame and Carlson18 and that of the US Preventive Services Task Force for determining effectiveness.19 The impact that repeated testing strategy recommended by the ADA8 had on diagnostic accuracy was analyzed using a clinical decision-making calculator.20 The positive predictive value (PPV) was calculated by specifying the probability of “true MA,” the sensitivity and specificity of the MA test, and simultaneously varying both the phi coefficients (for cases with “true” MA and without MA) from 0 (independence) to 1 (dependence). The phi coefficient is a measure of the correlation between the dichotomous results of 2 tests in the presence or absence of the target condition. Cost-effectiveness analyses were assessed with the quality checklist of 37 critical features developed by Gold and colleagues.21
We retrieved 105 articles from the initial literature search and excluded 44 general review articles. The reference lists of the remaining 61 articles were reviewed to locate additional relevant articles. No controlled trials of screening to prevent progression to nephropathy or that compared sequential repeated screening strategies were identified. We found 31 articles that reported the performance of 1 MA screening test or more. Of these, 8 reported the characteristics of a quantitative test;22-29 22 reported the characteristics of a semiquantitative test;28,30-50 and 1 reported both.28 Our review is unlikely to be affected by publication bias, because a wide range of results were reported from varied international sources.
We used a variety of cutoffs in the studies that reported quantitative UAC or UACR, which precluded pooling test characteristics of most of these studies. Because of the striking heterogeneity among studies and the existence of at least 1 large study for the 2 most commonly studied semiquantitative tests, we did not pool the sensitivities and specificities. The sensitivity ranged from 56% to 100% and specificity from -81% to 98% for UAC of 20 mg per L or greater for quantitative tests Table 1. For morning urine samples, the pooled sensitivity was 75% (95% confidence interval [CI], 59-91) and the pooled specificity was 97% (95% CI, 94-99).23,26 Test performance was similar for all types of urine samples.
The sensitivity ranged from 51% to 100% and specificity from 21% to 100% for semiquantitative tests. Test performance was similar for all types of urine samples. Micral (Roche; Mannheim, Germany) was the most extensively reported semiquantitative test. A large (n=2228) multicenter study of the Micral II found a sensitivity of 96.7% and specificity of 71% to detect a UAC of 20 mg per L or greater by radioimmunoassay (RIA).42 The sensitivity of the Micro-Bumintest (Bayer; Pittsburgh, Pa) ranged from 60% to 100% and the specificity from 21% to 97%. A large (n=1186) population-based study of the Micro-Bumintest reported a sensitivity of 98.6% (95% CI, 97.5-99.6) and specificity of 85.1% (95% CI, 82.4-87.7) to detect a UAC of 30 mg per L or greater by RIA.48
There is often considerable interobserver variation in the evaluation of semiquantitative tests that involve colorimetric changes. Mogenson and colleagues42 found 93% concordance of Micral results from 538 samples. The sensitivity of the Micral varies when used by different operators: general practitioners, 66%; laboratory technicians, 91%; and trained nurses, 84%. Ten percent of physicians who were less familiar with procedures accounted for 44% of the misread strips.34 The Micral was not influenced by most potential interference factors,51 though it may be affected by freezing.38,40 Authors have reported high numbers of false positives47 and problems interpreting the results of the Micro-Bumintest tests.52,53
Frame and Carlson Criteria for Screening Tests
The 6 criteria of Frame and Carlson18 we applied to MA screening Table 2 were introduced in 1975. There is adequate evidence to suggest that screening for MA meets the first 4 criteria.4,54,55 Whether the test is acceptable to patients at a reasonable cost (criterion 5) and is cost-effective (criterion 6) is less certain.
Criterion 5: Tests must be acceptable to the patient and available at reasonable cost. A major limitation of any annual screening program is the proportion of false-positive tests that occur. During the first years of an annual screening program in a previously unscreened population with a high prevalence of disease, the proportion of false positives would be low. For example, in the first year of screening a population with a 40% prevalence of MA,14 using a test that is 90% sensitive and specific, the probability of having true MA after a single positive test would be 86% (the positive predictive value [PPV]). During subsequent years of a screening program, the prevalence of MA should approach the annual incidence of new disease, 1% to 4% per year.14 Therefore, the PPV of a single screening test in subsequent years could be expected to range from 8% to 27%.
To reduce the number of false positives, the ADA recommends that 2 of 3 screening tests be positive over a 3- to 6-month period before beginning treatment.7,8,56 However, the degree of improvement that can be expected depends on the correlation between repeated tests. Although the UAE measure (in mg/minutes) has a high variance (coefficient of variation ranging from 33%-52%),57 there is no published information on the correlation between errors on repeated screens when each is simply categorized as positive or negative for MA. However, Feldt-Rasmussen57 calculated the probability of correct classification above or below 20 mg per minute using 1 sample compared with the median of 3 samples. Using 1 sample, specimens below 11 mg per minute and above 40 mg per minute had a greater than 95% probability of correct classification. By using the median of 3 samples, specimens below 13 mg per minute and above 32 mg per minute had a greater than 95% probability of correct classification. Most would agree that this is a clinically insignificant difference.
We analyzed the performance of a theoretical UAE test repeated up to 3 times according to ADA recommendations (considered negative if the first test is negative, or else the majority of 3 tests).8 Assuming an individual test sensitivity of 90%, a specificity of 90%, and a 10% prevalence of MA, we performed a sensitivity analysis of the effect of varying the correlations between repeated tests Figure 1.20 This pretest probability was selected because it was between the estimate of 40% prevalence for the first year of screening and a 1% to 4% annual incidence of new disease. If the tests are completely independent (correlation=0), the probability of true MA if the multiple screen is positive is 84%, an improvement compared with the PPV of 50% for a single positive test. However, as the correlation (phi) between tests increases, the PPV of repeated testing decreases, approaching the PPV for a single test. To keep the PPV of repeated testing as high as 75%, the correlation between tests would have to be lower than approximately 0.1, which is quite unlikely. Thus, although MA screening tests are noninvasive and relatively inexpensive, current recommendations may impose a significant burden on patient management without necessarily improving diagnostic certainty.
Criterion 6: Incidence of disease must justify screening cost. Seven cost-effectiveness analyses of MA screening and treatment with ACEIs to prevent end-stage renal disease (ESRD) have been published Table 3.58-64 Five of these studies estimated the cost-effectiveness of MA screening in persons with type 1 diabetes.59-63 Three of these 5 studies59,60,63 that found screening to be cost-saving assumed perfect testing for MA. In 1 study that considered false-positive tests, the additional cost of screening for MA was $27,042 per quality-adjusted year of life (QALY) saved, compared with simply screening for hypertension or macroalbuminuria.61
Because the incidence of a costly outcome such as ESRD is higher for persons with type 1 diabetes, MA screening is likely to be cost-effective in this population.62 However, the cost-effectiveness of screening persons with type 2 diabetes for MA, only 5% to 10% of whom will develop ESRD, has recently been analyzed.58,64 These analyses assumed perfect screening characteristics, and one study64 considered only Pima Indians, who have a higher incidence of ESRD. MA screening saved QALYs and reduced costs compared with screening for macroalbuminuria, but routine use of ACEIs for all persons with type 2 diabetes was cost-effective ($7500/QALY) when compared with screening.58 No cost-effectiveness analysis to date has included false-positive tests and studied a more typical population.
We found no controlled trials of screening to prevent progression to nephropathy.3 Recommendations for screening persons with diabetes for MA are based on expert opinion; the evidence to support the specific components of these recommendations is lacking. Several studies have also demonstrated that UACR has little advantage over the measurement of UAC alone.25,29,47,65 Use of untimed urine samples avoids the need for 2 visits, collection equipment, the problems of inaccurate timing, urine storage at 4 °C, and transfer to laboratories.38
Semiquantitative MA tests are not favored by the ADA8 but have an accuracy similar to quantitative tests. Though they may not be reliable when used by untrained health care providers, high sensitivities and specificities can be obtained by personnel other than laboratory technicians.34 Semiquantitative tests have the important advantages of increased convenience and decreased cost, which may improve adherence to recommendations. Several authors have suggested that semiquantitative MA tests could at least substitute for the first quantitative test in a multiple test strategy,28,36,45,66 and the ADA position has recently shifted to allow semiquantitative tests if quantitative tests are not readily available.67
The Micral is the best studied test, appears reliable, and has a high sensitivity even at low UAC (20 mg/L). A pooled analysis of 10 previous studies of the Micral found a sensitivity of 92.3% and a specificity of 83.2%.68 Results from studies were included that investigated 24-hour urine samples; homogeneity among the studies was not tested. Two large studies found a sensitivity of 90.1% to 96.7% and a specificity of 71% to 87%.42,51 The Micro-Bumintest has good sensitivity but has been evaluated at a slightly higher cutoff UAC (30 mg/L), and the reliability has been questioned.47,52,53
MA screening clearly meets only 4 of the 6 criteria of Frame and Carlson. Current recommendations for MA screening require repeated testing that is onerous and probably does not improve diagnostic certainty. This strategy has not been compared with simpler strategies in a randomized controlled trial. In our analysis, at low prevalence the theoretical improvement in specificity is minimal and would not seem to justify the need for a criterion of 2 of 3 tests positive.
A number of studies have reported on the poor rate of screening persons with diabetes in primary care.69,70 In an academic family medicine center, Lawler and Viviani71 found that the patient-reported rate of MA screening was 43%. In a recent survey of primary care physicians, more than 40% reported screening no persons with type 2 diabetes for MA, and only 17% screened more than 50% of persons with type 1 diabetes.72 A recent analysis of insurance claims data for 4623 persons with diabetes found that only 2.1% of those without known nephropathy were tested for MA during the study year.73 This lack of adherence to even single annual screening tests raises questions of whether the screening strategy of repeated screening followed by treatment will effectively prevent diabetic nephropathy. Strategies that incorporate using a semiquantitative test first may mitigate adherence problems, but the feasibility of such strategies has not been evaluated. A practice-based trial comparing screening strategies is needed.
Because of the high incidence of nephropathy and ESRD, MA screening in patients with type 1 diabetes is probably cost-effective. Screening persons with type 2 diabetes for MA is less certain. Analyses have generally not considered imperfect testing or the impact of sequential testing strategies. Based on studies that have demonstrated delayed progression in persons with diabetes who have normoalbuminuria,74 3 cost-effectiveness analyses found that routine use of ACEIs compared favorably with MA screening.58,62,64 A cost-effective analysis that considered recommended testing strategies and imperfect screening would be useful.
MA is associated with a substantial risk of cardiovascular events.75 The recent Heart Outcomes Prevention Evaluation Study found that ACEIs lower the risk of death, heart attack, stroke, and other complications of diabetes mellitus in high-risk patients with known cardiovascular disease.76,77 Given the difficulties of changing patient and health provider behavior, a more compelling question, which we discuss in a subsequent article, is whether routinely prescribing ACEIs is more desirable than annual screening and treatment when MA is detected.
We would like to thank the many people who contributed their time reading and commenting on our manuscript. We also thank Alice Reed and Stacy Wigley for their help assembling and managing the reference databases for this review and for preparing some of the graphics.
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