The renin–angiotensin–aldosterone system and calcium-regulatory hormones

Abstract

There is increasing evidence of a clinically relevant interplay between the renin-angiotensin-aldosterone system and calcium regulatory systems. Classically, the former is considered a key regulator of sodium and volume homeostasis while the latter is most often associated with skeletal health. However, emerging evidence suggests an overlap in regulatory control. Hyperaldosteronism and hyperparathyroidism represent pathophysiologic conditions that may contribute to or perpetuate each other; aldosterone regulates parathyroid hormone and associates with adverse skeletal complications, and parathyroid hormone regulates aldosterone and associates with adverse cardiovascular complications. As dysregulation in both systems is linked to poor cardiovascular and skeletal health, it is increasingly important to fully characterize how they interact in order to more precisely understand their impact on human health and potential therapies to modulate these interactions. This review describes the known clinical interactions between these two systems including observational and interventional studies. Specifically, we review studies describing the inhibition of renin activity by calcium and vitamin D, and a potentially bidirectional and stimulatory relationship between aldosterone and parathyroid hormone. Deciphering these relationships might clarify variability in outcomes research, inform the design of future intervention studies, and provide insight into the results of prior and on-going intervention studies. However, before these opportunities can be addressed, more effort must be placed on shifting observational data to the proof of concept phase. This will require reallocation of resources to conduct interventional studies and secure the necessary talent.

Plasma parathyroid hormone and cardiovascular disease in treatment‐naive patients with primary hyperparathyroidism: The EPATH trial

“…However, we could not confirm these observations in multivariate analyses of a large cohort of 155 patients with pHPT . Of note, PTH levels are significantly modified by inhibitors of the renin‐angiotensin‐aldosterone system, diuretics, and the calcimimetic drug cinacalcet . In a post hoc analysis of the EVOLVE (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events) trial, cinacalcet led to a significant decrease in both SBP and diastolic BP.…”

Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism

“…Although a dose-related increase in mean plasma potassium with eplerenone was observed in this population of patients, eplerenone was well tolerated and no cases of severe hyperkalemia were documented. Accumulating evidence indicates a clinically relevant interplay between aldosterone and PTH [20][21][22]. PTH directly mediates aldosterone production by inducing calcium entry into adrenal zona glomerulosa cells by binding to PTH/PTH-related peptide receptors and voltage-gated L-type calcium channels, by initiating various signal transduction pathways, and by indirectly activating the renin-angiotensin system [23,24].…”

Hyperaldosteronism and cardiovascular risk in patients with autosomal dominant polycystic kidney disease

“…[24,63] Therefore, the deficiency of vitamin D may explain hypertrophy of the left ventricle and proliferation of vascular smooth muscle cells and favor atherosclerosis and endothelial dysfunction. [64] Furthermore, vitamin D deficiency predisposes to upregulation of the RAAS, indeed the vitamin D is a negative endocrine regulator of the RAAS by suppressing renin biosynthesis. [40,62–67] Vitamin D is also involved in glycemic control, lipid metabolism, insulin secretion, and sensitivity, explaining the association between vitamin D deficiency and metabolic syndrome.…”