Dr Sonali Shah( left) Endocrinologist at Monash Health and a PhD candidate at Hudson Institute of Medical Research, Clayton, Victoria.

Professor Peter Fuller( centre) Head of the endocrinology department at Monash Health and head of the Centre for Endocrinology and Metabolism at Hudson Institute of Medical Research, Clayton, Victoria.

Associate Professor Jun Yang( right) Head of the Endocrine Hypertension Service at Hudson Institute of Medical Research and an endocrinologist at Monash Health, Clayton, Victoria.

First published online on 10 May 2024

BACKGROUND

HYPERTENSION, defined as blood

pressure greater than 140 / 90mmHg, is the leading cause of premature death worldwide. 1, 2 In Australia, one in three adults has hypertension and this is the most common medical condition managed in primary care. 2, 3 Despite advances in pharmacotherapy, two in three people with hypertension are not well controlled. 2 This is likely because of inter-individual differences in response to each class of antihypertensive. 4 Hypertension is better thought of as a multisystem syndrome with abnormalities in the vascular, renal and endocrine systems culminating in excess salt and water retention and vascular remodelling.

Treatment targeting the underlying aetiology of hypertension for an individual is key to effectively lowering blood pressure and reducing cardiovascular and renal injury. 5

A well-known regulator of blood pressure is the renin-angiotensin-aldosterone system( see figure 1). The presence of low renin in an individual with hypertension may be an

indicator of dysregulation of this system, that is, renin-independent excess salt and water resorption and an expanded volume state. Low renin hypertension( LRH) as a subtype of hypertension was first identified when plasma renin activity assays became available in the 1960s. LRH is common and found in up to one in three people with hypertension. 6

With the increased awareness of prevalence of primary aldosteronism( PA) in the community and easier access to assays, renin( and aldosterone) measurements are more commonly ordered, with a reported 40 % increase in the past five years( JG, DiaSorin Australia Pty Ltd, personal communication 28 July 2023). 7 However, the implications of low renin on its own and targeted treatment options are rarely discussed in hypertension guidelines. 8, 9

This How to Treat seeks to provide GPs with insight into renin physiology, the implications of finding a low renin concentration in their patients with hypertension and provide a pragmatic approach to patient management.

RENIN

RENIN is an enzyme produced mainly in the juxtaglomerular cells of the macula densa( see figure 2) in the afferent arterioles of renal tubules. It controls the renin-angiotensin-aldosterone system, which is important for the regulation of salt, water and blood pressure. 10 There are three main mechanisms that regulate renin secretion( see box 1).

In the presence of low salt, low blood pressure and sympathetic stimulation, renin is secreted and converts angiotensinogen to angiotensin I. This is in turn activated to angiotensin II by angiotensin-converting-enzyme( ACE)( see figure 1). Angiotensin II activates several compensatory mechanisms to maintain blood pressure including vasoconstriction, the release of antidiuretic hormone( vasopressin) from the posterior pituitary and aldosterone synthesis in the adrenal cortex.

Antidiuretic hormone acts on the collecting tubule in the nephrons to increase water resorption and, at high concentrations, it also causes vasoconstriction. Aldosterone-mediated mineralocorticoid receptor( MR) activation causes an increase

Box 1. The three main mechanisms that regulate renin secretion

• Salt status— Macula densa signalling via prostaglandin and nitric oxide release is regulated by sodium chloride concentration in the distal convoluted tubule of nephrons in the kidney.

• Blood pressure— Renin baroreceptor activation in response to a fall in renal perfusion.

• Sympathetic stimulation— Beta-1-adrenergic stimulation via noradrenaline by direct activation of renin-secreting cells and indirectly by renal hypoperfusion as a result of vasoconstriction of preglomerular arteries. 11

in sodium resorption in the distal nephrons of the kidney via the sodium chloride symporter and the epithelial sodium channel, which in turn causes loss of potassium.