Cardiovascular risk assessment and diagnostic work-up in rare diseases: focus on hyperaldosteronism and primary antibody deficiency

Introduction: Unilateral form of primary aldosteronism (PA) is the main curable cause of endocrine hypertension cause of PA and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of unilateral PA. The in vitro evidences of macrolide antibiotics specifically inhibit the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of unilateral PA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated unilateral PA. Aim: To test the effect of roxithromycin on aldosterone secretion and blood pressure in vivo in patients without PA, and in those with PA subtyped by AVS and examined according to the presence or absence of KCNJ5 mutation. Methods: We enrolled consecutive hypertensive patients undergoing screening for secondary hypertension, from January 2018 to June 2022. Each patient received a single oral dose of roxithromycin and, after the diagnostic work-up, baseline values of plasma aldosterone concentration (PAC) and blood pressure were compared with post-roxithromycin values. Next- generation sequencing (NGS) was used to identify KCNJ5 mutated from wild-type forms of unilateral PA. Response to roxithromycin was compared between non-PA, non-unilateral PA and unilateral PA. In unilateral PA we focused on KCNJ5 mutated vs wild-type patients. Results: After roxithromycin administration, patients with unilateral PA carring KCNJ5 mutation showed a decrease in PAC (p=0.030) that did not occur in unilateral PA KCNJ5 wild-type. In these groups systolic blood pressure (SBP) and diastolic blood pressure (DBP) did not change in response to roxithromycin. However, in non-PA group a decrease in PAC was observed (p<0.001) with a decrease in plasma cortisol concentration (PCC) (p<0.001) and systolic (p<0.001) but not diastolic blood pressure. After adrenalectomy, roxithromycin did not induce any change in PAC in KCNJ5 mutated unilateral PA. Conclusion: Roxithromycin administration induces a decrease in aldosterone production in patients with KCNJ5 mutation but not in wild-type, confirming its ability in vivo to blunt aldosterone production by blocking the mutated Kir3.4 sodium channel without affecting wild-type forms. As the decrease in PAC in the same patients did not occur after adrenalectomy, the roxithromycin effect is unequivocally attributable to the KCNJ5 mutated unilateral PA.