Response to Is the Aldosterone:Renin Ratio Truly Reproducible?
This letter1 reveals some confusion on what is reproducible in clinical terms and a poor understanding of what the plasma aldosterone concentration to renin ratio (ARR) is used for, that is the screening of primary aldosteronism based on an arbitrary cutoff. In the largest prospective study available that used a conclusive diagnosis of aldosterone-producing adenoma as the referent, this cutoff was determined to be 25.86 (with plasma aldosterone concentration in nanograms per deciliter and plasma renin activity in nanograms per milliliter per hour).2 Therefore, the fact that, “the upper of the 2 ‘limits of agreement’ in plot B is 2.1” was high1 is totally irrelevant, because any value exceeding this cutoff is considered to suggest the presence of primary aldosteronism and it does not really matter if the ARR is 2- or 200-fold higher than the cutoff.3
According to Bland and Altman,4 the Pearson correlation coefficient should be reported as a measure of the strength of the relation between variables (the ARR) followed by the Bland-Altman plot. The latter was intended as a “graphical presentation of agreement” between methods4 and not to estimate prediction, although it also gives the mean and 95% range of the differences, which Bland and Altman called the “95% limits of agreement.”4 According to them, “it is most unlikely that different methods will agree exactly, by giving the identical result for all individuals.”4 Undoubtedly this could even be truer for the ARR given the well-known within-assay and interassay variabilities of the plasma aldosterone concentration and the plasma renin activity assay, for example, the numerator and denominator of the ARR. Our study clearly showed that such anticipated differences between ARR exist.5 By recapitulating the underlying mathematics, these authors1 did nothing else than to stress our findings.5
As pointed out, only 7% of the patients fell outside the agreement interval, because renin was disproportionally high in the first as compared with the second ARR. This could be attributed to several reasons, as we discussed in depth.5 Had we excluded these outliers, the agreement interval between ARR would have been even smaller. As Bland and Altman stated, “… if differences are not clinically important (a decision not based on any probability value), one can therefore conclude that the two methods do show sufficient agreement to be used interchangeably.”4
Clinically, however, the diagnostic accuracy of the ARR can be conclusively judged from the receiver operating characteristic curve analysis and not from the Bland-Altman plot. The receiver operating characteristic curves (Figure 2 in Reference 5) of the ARRs were superimposable for identifying aldosterone-producing adenoma;5 at formal comparison, their areas under the curve were statistically equal, indicating that the ARRs furnished identical results. As we reported, no single case of aldosterone-producing adenoma identified with the first ARR was missed with the second ARR and vice versa. Importantly, adrenalectomy, on the basis of either ARR, resulted into a cure of primary aldosteronism and hypertension in all of the patients. Hence, our conclusions that clinically the ARRs showed “reasonably consistent results” and, despite being performed on average 4 weeks apart, they showed a “good within-patient reproducibility”5 were well supported by the data.
In summary, the points raised in this letter1 do not add any novel insight to what was already in our article.
Sources of Funding
This study was supported by research grants from the Foundation for Advanced Research in Hypertension and Cardiovascular Diseases, the Società Italiana dell’Ipertensione Arteriosa, and Progetti di Ricerca di Interesse Nazionale 2007PRELCC_002. Moreover, the study was supported by the research grants 60% to A.C.P., G.P.R., T.M.S. and Progetto di Ateneo to T.M.S.
Woodman RJ, Mangoni AA. Is the aldosterone: renin ratio truly reproducible? Hypertension. 2010; 55: e18.
Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A, Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni D, Rossi E, Boscaro M, Pessina AC, Mantero F, for the PAPY Study Investigators. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006; 48: 2293–2300.
Rossi GP, Seccia TM, Palumbo G, Belfiore A, Bernini G, Caridi G, Desideri G, Fabris B, Ferri C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Patalano A, Rizzoni D, Rossi E, Pessina AC, Mantero F, for the Primary Aldosteronism in the Prevalence in hYpertension (PAPY) Study Investigators. Within-patient reproducibility of the aldosterone: renin ratio in primary aldosteronism. Hypertension. 2010; 55: 83–89.