American Journal of Epidemiology Advance Access originally published online on August 25, 2006
American Journal of Epidemiology 2006 164(8):731-732; doi:10.1093/aje/kwj273
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Response to Invited Commentary |
Gansevoort et al. Respond to "Using Measures of Albumin Excretion"
1 Department of Nephrology, University Medical Center, Groningen, the Netherlands
2 Department of Clinical Pharmacology, University Medical Center, Groningen, the Netherlands
Correspondence to Dr. Ronald T. Gansevoort, Department of Nephrology, University Medical Center, P.O. Box 30.001, Groningen 9700 RB, the Netherlands (e-mail: R.T.Gansevoort{at}int.umcg.nl).
Received for publication May 4, 2006. Accepted for publication May 15, 2006.
We thank Dr. Dyer for his very thoughtful invited commentary (1
) on the report we wrote on which measure of urinary albumin excretion to use (2). His reaction contains valuable methodological information, among others, that the within-person coefficient of variation in urinary albumin measures should probably be better calculated after log-transformation. Being involved ourselves in a large-scale epidemiologic study designed to assess the impact of albuminuria in predicting renal and cardiovascular disease progression (www.PREVEND.org), we would like to emphasize that we share with Dr. Dyer a common interest, that being improvement in knowledge on how to measure and express albuminuria.
Because albumin excretion is currently drawing much attention in the medical literature as an evolving risk marker for atherosclerosis-related endpoints, it is of great importance that methodological issues are elucidated on what is the best measure of assessing urinary albumin excretion. We agree with Dr. Dyer that, in large-scale epidemiologic studies and also in clinical practice, 24-hour urine collections are difficult to perform and that, for this reason, alternatives should be sought. Although, in guidelines, use of the albumin:creatinine ratio is commonly advocated over use of the urinary albumin concentration (3–5), there are limited data available showing that indeed the albumin:creatinine ratio performs better and is worth the extra costs involved with measuring the urinary creatinine concentration. The data provided by Dyer et al. (6) indicate that the urinary albumin concentration is as good as the albumin:creatinine ratio in epidemiologic studies that use urine samples that have been stored frozen at –20°C for a long period.
The ultimate question to be answered is, however, what measure of urinary albumin excretion to use in daily clinical practice. We, of course, acknowledge that this was not the objective of the study by Dyer et al. (6), but it was our motivation to react to their article. In this respect, we recently published data concluding that in population screening the diagnostic performance of measuring the urinary albumin concentration in a fresh spot morning urine sample (first morning void) in predicting microalbuminuria in subsequent 24-hour urine collections is satisfactory and comparable with that of measuring the albumin:creatinine ratio in that same urine sample (7). In order to keep the costs involved in population screening for microalbuminuria as low as possible, we therefore proposed measuring only the urinary albumin concentration in a spot morning urine sample. This is fully in line with the conclusion of Dyer et al. (6). When the urinary albumin concentration exceeds a certain level, subjects should be asked to carry out additional urine collections to confirm the presence of microalbuminuria. Our advice is not to use the traditional cutoff value for a spot urinary albumin concentration of 20 mg/liter, but a somewhat lower value (e.g., 10 mg/liter) in order not to obtain too many false negative results (7). Of note, our study focused on what urinary albumin measure to use for screening subjects for the presence of microalbuminuria.
Which urinary albumin measure to use for follow-up of individual patients over time, for instance, to assess the effect of cardioprotective treatment (8), is another issue. The data of the post hoc analysis of the Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND-IT study) that we presented in our report (2) indicate that the urinary albumin concentration for this specific purpose performs perhaps not as well as the albumin:creatinine ratio. Our data are hampered by methodological difficulties, as we are the first to admit. We would therefore like to repeat our cautionary note that, to definitively answer this question, carefully designed prospective studies are needed. In our opinion, such studies should take the following into consideration.
- Fresh urine samples should be used, as this reflects clinical practice, and since it has been shown that prolonged storage at –20°C results in a systematic decrease in the albumin concentration and in an increase in variability of the albumin measurement (9). Furthermore, prolonged freezing might have differential effects on the urinary creatinine concentration. Whether these drawbacks apply also to short-term freezing and/or storage at –80°C has not been clarified. These considerations suggest that results of studies that use frozen urine samples cannot be easily extrapolated to clinical practice where fresh samples are used.
- When it is to be decided if the "gold standard" of 24-hour urinary albumin excretion can be replaced by determining the albumin concentration or the albumin:creatinine ratio in a spot morning urine sample, studies should make a comparison of these variables in specifically collected urine samples. Such studies should not use a portion of a 24-hour collection as a surrogate for a spot morning urine sample. Urinary albumin excretion follows a circadian rhythm. The urinary creatinine excretion when expressed as mmol/hour perhaps may not but, when it is expressed as mmol/liter, it certainly does follow a circadian rhythm (10). The morning urine is usually more concentrated than the urine during the day. A person's albumin concentration and albumin:creatinine ratio are therefore expected to be different when these values are obtained from a spot morning urine sample or from a portion of a 24-hour urine sample. Such differences are to be expected to influence results, especially when defining cutoff values. Furthermore, these data indicate that, in an individual subject, follow-up spot urine samples should be collected around a specific time and not on one occasion in the morning and on another in the afternoon.
- The ultimate point to take into consideration in the discussion on which measure of urinary albumin excretion should be used in clinical practice will be which of the three performs best in predicting cardiovascular and renal endpoints. To our knowledge, such a study has yet to be published.
We hope that the discussion presented in this issue of the Journal may be of interest and help to interpret studies on this important clinical topic.
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ACKNOWLEDGMENTS |
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Conflict of interest: none declared.
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References |
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 TOP References |
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- American Diabetes Association. Diabetic nephropathy. Diabetes Care 2002;25(suppl 1):S85–9.
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[Abstract/Free Full Text] - Dyer AR, Greenland P, Elliott P, et al. Evaluation of measures of urinary albumin excretion in epidemiologic studies. Am J Epidemiol 2004;160:1122–31.
[Abstract/Free Full Text] - Gansevoort RT, Verhave JC, Hillege HL, et al. The validity of screening based on spot morning urine samples to detect subjects with microalbuminuria in the general population. Kidney Int 2005;94(suppl):S28–35.
- de Zeeuw D. Albuminuria, not only a cardiovascular/renal risk marker, but also a target for treatment? Kidney Int 2004;66(suppl):S2–6.
- Brinkman JW, de Zeeuw D, Duker JJ, et al. Falsely low urinary albumin concentrations after prolonged frozen storage of urine samples. Clin Chem 2005;51:2181–3.
[Free Full Text] - Dyer AR, Stamler R, Grimm R, et al. Do hypertensive patients have a different diurnal pattern of electrolyte excretion? Hypertension 1987;10:417–24.
[Abstract/Free Full Text]
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Related articles in Am. J. Epidemiol.:
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