Primary aldosteronism: considerations about the evaluation of the aldosterone to renin ratio during canrenone treatment

Abstract

Recently Rossi and coll. have published an interesting study on the measurement of the aldosterone to renin ratio (ARR) during treatment with canrenone, for the diagnosis of primary aldosteronism (PA) [1]. This approach to the diagnosis of PA avoids the risk related to the withdrawal of antihypertensive treatment and to hypokalemia. The authors conclude that treatment with canrenone at doses that effectively controlled hypokalemia and blood pressure values did not preclude the diagnosis in PA patients, while the addition of the angiotensin type 1 receptor blocker olmesartan raised the false negative rate, reducing the ARR. The guidelines of the Endocrine Society and of other Societies suggest discontinuing mineralocorticoid receptor antagonists (MRA) for at least 4–6 weeks before the evaluation of ARR and the results of the study are in contrast with those considered valid until now [2, 3]. Canrenone, the main metabolite of spironolactone, has a lower affinity for mineralocorticoid [4] and androgen [5] receptors compared to spironolactone but despite this, it is effective in the treatment of PA and of resistant hypertension. For this reason canrenone, which has a lower cost than eplerenone, is used in some countries as MRA, while spironolactone is predominantly prescribed as an antiandrogen in polycystic ovary syndrome or in transgender women, considering its powerful antiandrogen and anti-inflammatory action [6]. The long-term consequence of binding of canrenone to mineralocorticoid receptors is a volume depletion, a stimulation of the renin-angiotensin system and the result in a secondary hyperaldosteronism. The activation of renin in PA is not immediate, but probably needs a period, given the long-term suppression of renin-angiotensin system in PA and the lower affinity of canrenone for mineralocorticoid receptors. The study of Rossi and coll. reports a persistent suppression of renin after 1 month of treatment with canrenone in almost all the ten cases with idiopathic PA [1], but we are wondering whether the results are due to the short-term treatment. The explanation that this effect of canrenone is related to the lack of hepatic metabolism is not plausible, considering that canrenone is a metabolite of spironolactone. The effects of MRA are complex and do not involve only the binding to mineralocorticoid receptors as antagonist. We have reported that in PA patients, spironolactone decreases the concentration of aldosterone in the first period of treatment, when renin is still suppressed acting directly at the level of aldosterone synthase in the adrenal glomerulosa [6, 7]. Even Rossi and coll. reported that three patients (9.4%) among those with unilateral PA presented a reduction of aldosterone values after 1 month of canrenone, leading to a case of false negative ARR [1]. This effect is transient, and the subsequent activation of renin leads an increase of both renin and aldosterone values. Other studies have reported that canrenone, potassium canrenoate or spironolactone are able to resolve some cases of idiopathic PA after long time treatment [8–10]. We have also shown that canrenone is able to block directly the effect of aldosterone excess at the level of human mononuclear leukocytes in vitro, reducing cell volume, regulating the intracellular concentration of sodium and potassium, and blocking the inflammatory effect [11–13]. The activation of the renin angiotensin system due to volume depletion at the level of iuxtaglomerular apparatus needs more time than 1 month of treatment in PA [14, 15], as the affinity of canrenone for mineralocorticoid receptors is lower than that of spironolactone [4, 5]. In our experience after more prolonged treatment, the depletion of volume increases renin and aldosterone as reported during spironolactone treatment [14, 15]. The evaluation of the ARR after 2 months with canrenone associated to olmesartan in the study of Rossi and coll. showed a lower ARR value with false negative results in * D. Armanini [email protected]