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Letters to the Editor |
Departments of1 Clinical Chemistry and2 Nephrology and Hypertension, University Hospital of Liege, University of Liege, Liege, Belgium
aAddress correspondence to this author at: Service de Chimie Médicale, Centre Hospitalier Universitaire de Liège, Domaine du Sart-Tilman, B-4000 Liège, Belgique. Fax 32-4-3667691; e-mail Etienne.cavalier{at}chu.ulg.ac.be.
To the Editor:
The Editorial by Stowasser and Gordon recently published in Clinical Chemistry is commendable (1). We fully agree with their reservations on the use of commercial assays by inexperienced laboratories and their point that patient management decisions should not be based on a single measurement of the ratio of aldosterone to plasma renin activity (ARR). We would like to reinforce this point by demonstrating the important influence of analytical variation on ARR measurement results.
Plasma renin activity (PRA) is evaluated as the difference in angiotensin I production by the enzyme at 37 °C and endogenous angiotensin I, estimated by a determination of angiotensin I at 4 °C. Therefore the CV of the assay is determined by the variations of the measurements at 37 °C and 4 °C.
To evaluate the impact of these assay variations on the ratio results, we performed 5 PRA determinations during a 5-week period on 2 samples with activities of 
0.6 and 0.7 µg/L/h. The samples were divided into aliquots and kept at –80 °C until analysis. Using the RENCTK reagent set (Diasorin) according to the manufacturer’s instructions, 4 well-trained and experienced technicians (with an average work experience of 26.8 years) performed the tests along with routine PRA determinations. The results are presented in Table 1
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Given the effect of analytical variation on the mean values obtained and using the highest value possible at 37 °C with the lowest value at 4 °C and vice versa, PRA values would range from 0.44 to 0.81 µg/L/h for sample 1 and from 0.58 to 0.89 µg/L/h for sample 2. If these values occurred in patients with slightly increased supine aldosterone (e.g., 200 ng/L), with an acceptable CV of 10% for aldosterone measurement, the ARR would range from 22 to 50 for patient 1 and from 20 to 38 for patient 2. Therefore, even with major differences in the criterion for a raised ARR (2), the width of the grey zone around the threshold value allows a patient result to be indiscriminately considered as "normal" or "pathologic" based on a single sample.
This approach, it may be argued, is purely analytical, and a slight degradation of angiotensin I over time could have had an important impact on the low values measured in this study. Moreover, endogenous angiotensin I concentrations are below the first quantifiable point of the curve and perhaps should not be reported. Nevertheless, many studies published on screening for primary aldosteronism either did not consider PRA analytical variation or underestimated it because activities in the samples used for estimating between-assay variation were much higher than 0.6 or 0.7 µg/L/h, leading to lower CVs (3). Even if accuracy of the assay can be improved for values <1 µg/L/h by incorporating a long incubation (18 h) (4), PRA determination is and will remain very difficult because of the important effects of pH, time, and temperature conditions and the combined variation of 2 angiotensin I determinations, sometimes at very low concentrations.
Our results emphasize that ARR determined on a single blood sample should not be used for primary aldosteronism screening. The value of performing a 2nd ARR determination to reduce the uncertainty associated with a single ARR measurement should be evaluated in a prospective study. Nevertheless, we believe that because of analytical variation a grey zone will always exist around the clinical threshold.
References
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