28 HOW TO TREAT: LOW RENIN HYPERTENSION
28 HOW TO TREAT: LOW RENIN HYPERTENSION
31 OCTOBER 2025 ausdoc. com. au
Further renin release is inhibited via negative feedback by activation of the angiotensin II type 1 receptor in the juxtaglomerular apparatus. A suppressed renin suggests the presence of a high salt and an expanded volume status.
How is renin measured?
There are two ways to measure renin( see box 2).
Interpretation of renin in the context of hypertension
Renin concentrations vary in response to physiological stimuli and medications( see box 3). Where possible, it is best to measure renin in the morning, in a seated position, and in the absence of medications that interfere with its concentration. If antihypertensive agents are being changed to facilitate testing( see table 1), closely monitor this to ensure adequate control of blood pressure. 14 The Endocrine Society of Australia has a practical online guide on switching to noninterfering antihypertensive agents.
Renin is considered low if direct renin concentration is less than 8.2-12mU / L( plasma renin activity less than 1ng / mL / hr) and elevated if above the upper limit of normal for the laboratory reference range. In the context of hypertension, renin can be elevated in renovascular hypertension, renin-secreting tumours, and malignant hypertension. More commonly, renin is increased by antihypertensive drugs such as ACEIs, ARBs and diuretics. This article concentrates on the approach to patients with LRH.
When to measure plasma renin
Current recommendations are to measure renin when PA is suspected. 8
High-risk populations for PA include patients with sustained blood pressure greater than 150 / 100mmHg, resistant hypertension, controlled hypertension requiring four or more antihypertensive agents, hypokalaemia, an adrenal incidentaloma or a family history of stroke below the age of 40 or a first-degree relative with PA. 12
However, there is emerging evidence to support the screening of all patients with hypertension for PA( see later) before starting antihypertensive therapy. 15 This is based in part on the increased evidence for how common PA is in primary care and the added complexity of interpreting renin and aldosterone on interfering antihypertensives or difficulties associated with switching to non-interfering medications.
PREVALENCE AND CAUSES OF LOW RENIN HYPERTENSION
IT is estimated that one in three people with hypertension will have low renin. 6
The most common identifiable cause of LRH is PA. Rare causes include monogenetic diseases and cortisol excess. Importantly, a large proportion of LRH is currently undefined( see figure 5).
Primary aldosteronism
PA, also known as Conn’ s syndrome, is the most common cause of LRH, and is estimated to be the cause of LRH in one in four patients. 6, 7, 16-18
↓ Blood pressure / salt sympathetic stimulation
↑ Antidiuretic hormone
Water resorption
PA is characterised by unregulated aldosterone production by one( aldosterone-producing adrenal adenoma [ see figure 6 ], or very rarely, carcinoma) or both adrenal glands( bilateral adrenal hyperplasia or bilateral adrenal adenomas). Excess aldosterone causes MR activation, salt and water retention and
ACE
Figure 1. Renin-angiotensin-aldosterone system and its role in salt, water and blood pressure homeostasis. MR: mineralocorticoid receptor.
↑ Renin
Table 1. Suggested non-interfering medication Medication Sustained-release verapamil Moxonidine Prazosin Hydralazine Source: Gurgenci T et al 2020 14
Box 2. Measurement of renin
Oral dose 180-240mg daily 200-400μg daily 0.5mg bd— 5mg tds
Angiotensinogen
↑ Angiotensin I
↑ Angiotensin II
12.5mg bd— 50mg tds
↑ Aldosterone
MR activation
Sodium reabsorption
↑Blood volume / salt and pressure
• Direct renin concentration( DRC):— This measures the amount of actual renin present using an automated chemiluminescence immunoassay.— Units for DRC are ng / L or mU / L.— This method involves incubating samples with monoclonal antibodies specific to renin.— DRC immunoassays are available at most major laboratories in
Australia and have a quick turnaround time with high throughput.
• Plasma renin activity( PRA):— This measures the enzymatic activity of renin in a given volume of plasma by measuring the amount of angiotensin I produced in a specific amount of time after adding angiotensinogen.
— Units for PRA are ng / mL / hr or fmol / L / sec where ng or fmol quantifies the amount of angiotensin I.
— PRA is not widely available in Australia and is more labour-intensive with a longer turnaround time.
Note: DRC and PRA have a reasonable correlation; an estimated conversion of PRA 1ng / mL / hr
12, 13
≈ plasma renin concentration 8.2-12mU / L has been proposed.
vascular remodelling. Studies from various countries report a prevalence between 5-11 % in patients with hypertension in primary care. 16-18 A recent prospective study in Victoria found that 14 % of treatment naïve patients with hypertension screened by GPs had PA. 7
Clinical characteristics of
Vasoconstriction
Increase in peripheral resistance
patients with PA are often indistinguishable from those of patients with essential hypertension. A clue to diagnosis may be that blood pressure is less responsive to standard antihypertensives( ACEIs, ARBs, calcium-channel blockers and beta blockers). 12 Spontaneous hypokalaemia in patients with hypertension may be a hint but most patients with PA have a potassium concentration within the reference range.
It is vital to make a timely diagnosis( see box 4) as untreated PA confers a higher risk of cardiovascular disease, chronic kidney disease and mortality compared with those with essential hypertension after adjusting for age, sex and blood pressure. 19-21
The most reliable method for screening for PA is an aldosteronerenin ratio( ARR). 12 Pathology laboratories calculate this by dividing aldosterone by the renin concentration. An ARR greater than 70pmol / mU( or greater than 50pmol / mU in some laboratories) is positive and considered suggestive of underlying PA. Consider a referral to an endocrine hypertension clinic for further testing, including confirmatory tests such as the saline suppression test. There are targeted treatment options available for PA that are effective in reducing both blood pressure and cardiovascular risk. 22 This includes surgical resection of the culprit adrenal gland in the case of a unilateral aldosterone-producing adrenal adenoma or MR antagonists( MRAs) to block the action of aldosterone in patients with bilateral adrenal hyperplasia or those who are not suitable for surgery.
Box 3. Factors that affect renin concentrations
• Factors that reduce renin:— High salt intake.— Liquorice.— Oestrogen-containing oral contraceptive pill / menopausal hormone therapy( direct renin concentration only).— Beta blockers.— Central agonists.— NSAIDs.— Advancing age.
• Factors that increase renin:— Upright posture.— Hypokalaemia.— Calcium-channel blockers.— Renin-inhibitors( but reduces plasma renin activity).— Diuretics.— ACEIs / ARBs.— Renal artery stenosis( see figures 3 and 4). Source: Funder JW et al 2016 12
Box 4. Three steps to diagnosing primary aldosteronism
• Screening:
— Screen for excess aldosterone production using plasma ARR; ARR greater than 70pmol / mU is considered abnormal in most laboratories.
• Confirmation:
— Confirm autonomous aldosterone production with one or more tests if the ARR is elevated; these include saline suppression test, fludrocortisone suppression test, oral salt loading test or captopril challenge test.
• Subtyping:— Confirm whether aldosterone excess is unilateral or bilateral with adrenal vein sampling and adrenal CT to guide further management.
Recent studies have demonstrated that autonomous aldosterone production occurs on a continuum and may initially appear in patients with normal blood pressure or less marked elevations in aldosterone. 23 Current screening and diagnostic thresholds for PA may not fully capture the early stages of this continuum. Low renin may be a sensitive indicator of the underlying pathophysiology. 23 At present, research is being undertaken to explore this continuum as well as optimal methods of identifying the disease in its earliest stages( see box 1).
Rare causes of low renin hypertension
Rare causes of LRH with an estimated prevalence of less than 2 % include monogenetic causes and cortisol excess. The clinical features and underlying disease processes are summarised in table 2.
If patients present with LRH at a young age with a positive family history, consider a differential diagnosis of monogenetic causes of hypertension and a referral to a nephrologist. Definitive diagnosis can be made with genetic testing. If there are clinical features of excess cortisol or androgen, or absence of secondary sexual characteristics,