Current Issues in Measurement and Reporting of Urinary Albumin Excretion
National Kidney Disease Education Program-IFCC Working Group on Standardization of Albumin in Urine



Background: Urinary excretion of albumin indicates kidney damage and is recognized as a risk factor for progression of kidney disease and cardiovascular disease. The role of urinary albumin measurements has focused attention on the clinical need for accurate and clearly reported results. The National Kidney Disease Education Program and the IFCC convened a conference to assess the current state of preanalytical, analytical, and postanalytical issues affecting urine albumin measurements and to identify areas needing improvement.
Content: The chemistry of albumin in urine is incompletely understood. Current guidelines recommend the use of the albumin/creatinine ratio (ACR) as a surrogate for the error-prone collection of timed urine samples. Although ACR results are affected by patient preparation and time of day of sample collection, neither is standardized. Considerable intermethod differences have been reported for both albumin and creatinine measurement, but trueness is unknown because there are no reference measurement procedures for albumin and no reference materials for either analyte in urine. The recommended reference intervals for the ACR do not take into account the large intergroup differences in creatinine excretion (e.g., related to differences in age, sex, and ethnicity) nor the continuous increase in risk related to albumin excretion.

Discussion: Clinical needs have been identified for standardization of (a) urine collection methods, (b) urine albumin and creatinine measurements based on a complete reference system, (c) reporting of test results, and (d) reference intervals for the ACR.

current practices that reflect the consensus opinions of the conference participants
1. Use of the term "urine albumin" is recommended; "microalbumin" is discouraged.

2. First morning void urine samples provide lower variability than random samples.

3. Second morning void urine samples may also be acceptable but there is no evidence to support this practice as superior to first morning void.

4. Urine albumin should be measured in urine that has not been frozen. Albumin in urine is adequately stable when stored at 2–8 °C for 7 days before measurement. Any cloudiness due to precipitate or cellular components should be removed by centrifugation before refrigerated storage.

5. Refrigerated urine should be warmed to room temperature before measurement to dissolve precipitates that may have formed and adsorbed albumin. The urine should be visually examined for precipitate and centrifuged if necessary to remove residual precipitate.

6. If urine is to be frozen before measurement, it should be frozen at –70 °C. Any cloudiness due to precipitate or cellular components should be removed by centrifugation before frozen storage. Thawed samples should be warmed to room temperature and mixed thoroughly before measurement. The effect of freezing and thawing on albumin molecular forms is not thoroughly understood.

7. An albumin/creatinine ratio should be reported with all urine albumin measurements.

8. Confusion arises from reporting results in units of "mg albumin/mmol creatinine," "g albumin/mol creatinine," "mg albumin/g creatinine," or "µg albumin/mg creatinine." This situation reflects national or regional preferences and is not likely to be resolved. Ideally, International System of Units should be adopted. In the interim, uniform guidelines should be followed within a country or region.

9. Albumin concentrations reported in milligrams per liter are difficult to interpret and concentrations in these units should not be the only value reported.

issues requiring further investigation for standardization of measurement and reporting of urine albumin
1. Clarification of preanalytical requirements.

Influence of container type.

Influence of timing of collection (first morning, second morning, random, 24 h) related to biological variability.

Influence of blood (menstrual or urinary bleeding), seminal fluid, and other physiologic contaminants of urine.

2. Clarification of the molecular forms of albumin in freshly voided urine, and the definition of the measurand.

3. Clarification of the degree of urine albumin degradation under various conditions of storage.

4. Clarification regarding the variation in urinary matrix composition over which urine albumin measurement procedures must operate.

5. Clarification of the clinical requirements for total error in measurement of urine albumin.

6. Development of a reference measurement procedure.

7. Development of a urine albumin secondary reference material including its commutability validation and credentialing by JCTLM.

8. Development of a urine creatinine secondary reference material including its commutability validation and credentialing by JCTLM.

9. Identification of appropriate EQAS materials that will allow performance of routine methods to be compared.

10. Standardized measurement results are necessary to enable clinical studies to determine the optimal decision thresholds for AER and ACR.

11. Different decision limits may be needed for random vs first morning or other standardized collection time, owing to the increased variability of randomly collected samples.

12. The ACR varies with age, sex, and ethnicity. Decision thresholds suitable for these subgroups need further investigation. A single decision threshold may not be adequately sensitive for each subgroup.

13. Risk of chronic kidney disease and cardiovascular disease are continuous functions of urine albumin concentration. The appropriate thresholds for risk for given populations (e.g., general population or high risk groups such as diabetes, hypertension or cardiovascular disease) need to be determined.

14. Investigation of the usefulness of age- and sex-specific equations to convert ACR to an estimated AER for which a single reference limit may be appropriate.

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