Letter to the Editor from Zhu and Rossi: “Development and Validation of Criteria for Sparing Confirmatory Tests in Diagnosing Primary Aldosteronism”

To the Editor,

Wang et al would support the skipping “confirmatory” tests in patients with plasma aldosterone concentration (PAC) >20 ng/dL, plasma renin concentration (PRC) <2.5 mIU/L, and spontaneous hypokalemia (1). Primary aldosteronism (PA), the most common curable cause of arterial hypertension, is markedly underdiagnosed (2), partly because of the complexity and costs of the diagnostic workup. Therefore, the Endocrine Society and recent guidelines introduced a simplification of the workup by allowing skipping “confirmatory” tests when PA is biochemically florid, defined as PAC >20 ng/dL, spontaneous hypokalemia, and “undetectable” renin (3, 4), defined as PRC <2 mIU/L (3). This value is remarkably similar to that of Wang et al, who claimed that by using their PRC value, instead of 0.53 mIU/L that they stated to be recommended in the Endocrine Society Guideline, the sensitivity increased from 11% to 36% (1). But is this all gold that glitters? A head-to-head comparison of the chemiluminescence-based PRC assay with the plasma renin activity radioimmunoassay clearly showed that the former loses precision in the low value range of renin, that is, those typically occurring in PA. Hence, a 0.50 mIU/L difference between the Endocrine Society cutoff and the value proposed by Wang et al, in a range where the PRC assay does not perform optimally, should be considered with great caution (5).

What really matters for “confirmatory” tests is by no means sensitivity, but specificity, because they aim at sparing adrenal vein sampling, a technically challenging and poorly available procedure, to false positive patients at screening. At the prevalence rate of PA seen at referral centers (11%), the negative predictive value of these tests is about 3-fold higher than the positive predictive value (6), indicating that these tests work as “exclusion tests,” a conclusion supported by Wang’s study, where in both the development and the validation cohort the specificity of the confirmatory tests was 3- to 9-fold, respectively, higher than sensitivity.

According to the STARD methodology (7), novel diagnostic approaches should be validated against a gold standard, which for PA, is biochemical cure after adrenalectomy, not the confirmatory tests used by the authors, which introduced an obvious tautology bias in their analysis. Furthermore, they neither compared the accuracy of their approach with that in the Endocrine Society Guideline, nor did they determine accuracy and the optimal aldosterone-to-renin ratio (ARR) cutoff by the area under the receiver operator characteristic curve and Youden index analysis, the key tools for the question that they wished to investigate.

Finally, for case detection of PA what matters is the ARR, rather than PAC or PRC values alone. With the PAC >20 ng/dL and PRC <2.5 mIU/L suggested by Wang et al, the calculated ARR is >66 ng/dL/mg/mL/h (>80 ng/mIU, n.v. < 20.6). According to a very large study performed following the STARD methodology (7), such a value would offer a specificity close to 100% and a false positive rate near to 0%. Moreover, no diagnostic gain whatsoever could be accomplished with a confirmatory test (8).

Abbreviations

Abbreviations
 
• ARR

  aldosterone-to-renin ratio

 
• PA

  primary aldosteronism

 
• PAC

  plasma aldosterone concentration

 
• PRC

  plasma renin concentration

Additional Information

Disclosure Summary: The authors have nothing to disclose. The authors declared that they have no conflicts of interest to this work.