Liu et al 1 have reported an interesting study about renal denervation associated with unilateral adrenalectomy for treating or ameliorating post‐surgery resistant hypertension in patients with unilateral aldosterone‐producing adenoma.
Primary hyperaldosteronism is one of the most frequent causes of resistant hypertension (about 20% of cases). For that reason, the concept of resistant hypertension should be revisited, considering that aldosterone receptor blockers (MRA) are rarely used and in many cases, hypertension is resistant because MRA were not included in the therapy.
The origin of primary hyperaldosteronism is still unknown and must be considered a syndrome, with different mechanisms of origin. 2 Recently, mutations of the potassium or calcium channels, the activation of clusters bearing aldosterone synthase, or the presence of antibodies against aT1 receptor of angiotensin II have been highlighted. 3
Fifty percent of cases normalize blood pressure after successful surgery, while the remaining 50% have to continue a hypotensive therapy despite the fact that aldosterone and potassium have normalized. Normalization of pressure and potassium using MRA alone before surgery is considered a marker of complete recovery after surgery in APA.
The cause of persistence of hypertension after successful surgery is related either to a previous association with essential or secondary hypertension, or to a persistence of a chronic damage previously caused by aldosterone excess on the vessels, that persists despite the normalization of aldosterone and potassium.
A suggestive hypothesis is that of a progression from essential hypertension to idiopathic hyperaldosteronism and to adenoma but it is more likely that idiopathic hyperaldosteronism and unilateral adenoma are two different clinical manifestations of the syndrome. 2 In some cases, patients with idiopathic hyperaldosteronism recover completely also from hypertension after withdrawal of MRA used for 15‐20 years. 4 This effect is probably linked to the direct effect of spironolactone at the glomerulosa level, partially blocking aldosterone synthase. The same effect is also evident at the beginning of the therapy, when renin is still suppressed but, later, it is overcome by the activation of the renin‐angiotensin system due to sodium and volume depletion.
The study of Liu et al 1 reports that patients who need hypotensive therapy even after surgery have a beneficial effect by associating unilateral adrenalectomy with renal artery denervation (RD N), which is able to reduce the local and general sympathetic tone. This approach allows also to strip the tissue surrounding the renal artery, destroying most of the renal nerves distributed in the adventitia. The usual alternative using a catheter on the arterial intima could result in arterial damage and thrombosis. The novelty of the study is that denervation is performed from the adventitia to the lumen of the renal artery. This method is simpler and safer because it is performed by expert operators during laparoscopic unilateral adrenalectomy.
The post‐surgery evaluation showed a higher prevalence of recovery or amelioration of blood pressure control using fewer drugs. It is worth of note that the authors performed the RDN only in one renal artery and that the systemic effect was evident, consistent with a positive effect of a partial decrease of sympathetic tone at the level of renal arteries but also at the systemic level. These results highlight the possible interaction between aldosterone and the sympathetic system. It has been reported that aldosterone acts via genomic and rapid non‐genomic effects in target tissues bearing mineralocorticoid receptors. 2 , 5 These receptors are also found in the renal vasculature and in mononuclear lymphocytes, antagonizing the endothelial nitric oxide (NO) synthase when aldosterone is produced in excess. Genomic and rapid non‐genomic aldosterone effects increase renal vascular resistance and thereby mediate arterial hypertension, if endothelial dysfunction is present. A direct effect of antibodies against AT1 receptor could have a direct role in the sympathetic activation via angiotensin II receptors.
It is interesting to note that, both at the level of the vessels and at the level of the adrenal glands, the pro‐inflammatory effect of aldosterone activates inflammatory cytokines production and, as a consequence, decreases nitric oxide (NO) production thus activating the sympathetic system. This effect is clearly evident at the level of the renal arteries and their denervation has proven to be useful for an improvement in blood pressure control after surgery.
The use of MRA is able to improve the inflammatory state and cardiovascular risk in hypertensive patients regardless of the value of renin and aldosterone, and, therefore, the therapy of resistant hypertension should always include mineralocorticoid‐aldosterone (MRA). 6
The inflammatory reaction underlying the activation of the sympathetic system is induced by the arrival of mononuclear leukocytes, which, in turn, are regulated by MRA system. These cells have their mineralocorticoid receptors, and aldosterone has been seen to regulate both the concentration of intracellular electrolytes and the volume but also, when produced in excess, it can activate the inflammatory response which is at the origin of sympathetic system activation. 7 These effects are both genomic and non‐genomic and it seems that both are linked to the classic aldosterone receptor. The non‐genomic inflammatory effect has been demonstrated in erythrocytes that are anucleate. In such cells, an excess of aldosterone can damage the cellular membrane and activate the oxidative stress and these three effects are blocked by the co‐incubation with canrenone the active metabolite of spironolactone. 8 A similar membrane damage has been reported in primary hyperaldosteronism. 9
Post‐surgery biochemical and hormonal evaluation showed no significant difference between patients with adrenalectomy alone compared to those with added denervation.
It is difficult to evaluate renin and aldosterone after the intervention in the two groups. Hypotensive therapy causes different effects in relation to the assumed drugs. Diuretics increase renin and aldosterone, but ACE inhibitors increase renin and reduce aldosterone and so on. The sympathetic nervous system also interacts with the immune system by contributing to inflammation, leukocyte activation, extravasation, increased oxidative stress, and production of chemokines and cytokines. 10 , 11
The activation of the sympathetic system is confirmed by the current study that uses adventitious denervation and not by the intima that could cause irreversible damage.
The advantage of such an association is that it can be done directly with unilateral adrenalectomy. It is interesting that denervating a single renal artery effect at a distance is evident. Considering the role of the renal nerves in the regulation of renal function, the RDN can be considered an additive approach to better control blood pressure using less antihypertensive drugs in individuals with resistant hypertension and in patients operated for unilateral primary hyperaldosteronism. The effect of ablation is more evident after surgery considering that the renin‐angiotensin system is reactivated, and it is well known the role of angiotensin II in the activation of sympathetic system.
In conclusion, the study of Liu et al reports an interesting approach to the treatment of post‐adrenalectomy hypertension in aldosterone‐producing adenoma, but these results need a confirmation in a wider number of cases.
CONFLICT OF INTEREST
None.
AUTHOR CONTRIBUTIONS
DA, CS, AA, GA, and LB contributed to the conception of the work and interpretation of published data, drafted the manuscript, revised it critically and gave the final approval of the version to be published.
Armanini D, Sabbadin C, Andrisani A, Ambrosini G, Bordin L. Primary aldosteronism: Involvement of sympathetic system in the persistence of hypertension after surgery. J Clin Hypertens. 2020;22:1616–1617. 10.1111/jch.13964
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