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31 OCTOBER 2025 ausdoc. com. au dehydrogenase type 2( 11βHSD2) enzyme activity and subclinical hypercortisolism. 23, 38, 39 The common pathophysiology is excess MR activation and as such an MRA may be the treatment of choice to lower blood pressure in most of the patients with LREH.

In people of African descent, genes involved in sodium reabsorption in the proximal and distal nephrons of kidneys have been suggested as the cause of LREH. As a result, patients are more likely to retain salt and present with salt-sensitive hypertension. The treatment choice for such patients is thiazides or epithelial sodium channel inhibitors such as amiloride. 40

Further research is needed to better understand the pathophysiology of the hypertension and the optimal antihypertensive drug class to use in LREH. A randomised clinical trial assessing the efficacy of MRA treatment compared with standard practice is being undertaken at Victoria’ s Monash Health to understand if early targeted treatment with an MRA in LRH improves blood pressure and cardiovascular health in patients with LRH( see box 5). 41

APPROACH TO PATIENTS WITH LOW RENIN HYPERTENSION

FIGURE 9 presents a practical approach to the management of patients with LRH.

CASE STUDIES

Case study one

SIMON, a 45-year-old man, was diagnosed with hypertension three years ago by his GP. His mean seated clinic blood pressure was 152 / 99mmHg. His father was diagnosed with hypertension in his early 40s and developed AF and a stroke at the age of 50.

Table 2. Rare causes of low renin hypertension Disease Cause Clinical features

Familial hyperaldosteronism type I 24

Apparent mineralocorticoid excess 25-28

Liddle syndrome 29

Pseudohypoaldosteronism type 2( or Gordon syndrome) 30

Simon was started on prazosin 0.5mg twice a day as his doctor wanted to check his aldosterone and renin profile without interference from medications. His initial investigations appear in table 3. Given his ARR was greater than the threshold of 70pmol / mU( positive screening result for PA), he was referred for a saline suppression test to confirm

Autosomal dominant chimeric gene formation → aldosterone production is under the control of adrenocorticotropic hormone instead of angiotensin II

An autosomal recessive genetic mutation affecting 11-betahydroxysteroid dehydrogenase type 2 or acquired due to antifungals such as posaconazole and chronic intake of glycyrrhetinic acid, eg, liquorice

Autosomal dominant gain of function mutation affects subunits of the epithelial sodium channel in the distal nephron

Gain of function mutations affecting serine / threonine kinases, WNK1 and WNK4, which regulate the thiazide-sensitive sodium chloride cotransporter and cause an increase in sodium chloride resorption

for PA. His results were consistent with PA as aldosterone was not adequately suppressed after 2 litres of normal saline infusion, where the cut-off for the post-saline aldosterone is 170pmol / L. He was referred for further investigations for subtyping of PA.

He underwent an adrenal CT scan which showed a single 9mm adrenal

• Hypertension at a young age( younger than 20)

• Family history of PA or early-onset stroke( younger than 40)

• Biochemical results are the same as in PA

• Childhood-onset hypertension

• Low renin, low aldosterone and hypokalaemia

• Other: faltering growth, nephrocalcinosis, accelerated end-organ damage

• Elevated urinary metabolites tetrahydrocortisol and reduction in tetrahydrocortisone

• Hypertension in childhood / young age

• Low renin, low aldosterone and hypokalaemia

• Childhood-onset hypertension

• Low renin, low aldosterone and hyperkalaemia

Cushing’ s syndrome Excess circulating cortisol secondary to pituitary disease, adrenal( see figure 7) 32, 33 disease, ectopic disease, or exogenous cortisol / hydrocortisone use

Congenital adrenal hyperplasia 34

Excess cortisol overwhelms the ability of renal enzymes to inactivate cortisol at the MR thereby causing MR activation

Rare autosomal recessive forms of congenital adrenal hyperplasia characterised by the inability to synthesise cortisol due to 11-betahydroxylase or 17-alpha-hydroxylase deficiency with a consequent increase in deoxycorticosterone and / or 11-deoxycortisol, both of which activate the MR

An acquired form of 17-alpha-hydroxylase deficiency has been reported with abiraterone acetate, a medication used in the treatment of prostate cancer to reduce testosterone production 35

MR: mineralocorticoid receptor, MRA: MR antagonists, PA: primary aldosteronism, WNK: lysine deficient protein kinase

• Hypertension

• Low renin and low aldosterone

• Clinical features are multisystem including facial plethora, violaceous striae, central adiposity, proximal muscle wasting and bone loss, menstrual irregularities, low mood and dysglycaemia

• Hypertension at a young age

• Low renin, low aldosterone, and high deoxycorticosterone and / or 11-deoxycortisol

• Hyperandrogenism in 11-beta-hydroxylase deficiency and the absence of secondary sexual characteristics in 17-alpha-hydroxylase deficiency

Table 3. Simon’ s initial investigations Investigation and reference range Potassium( 3.5-5.2mmol / L) 3.6 Plasma renin concentration mU / L( 4.4-46) 5.0 Aldosterone pmol / L( 70-1090) 521 ARR pmol / mU( less than 70) 104

Simon’ s results

Dr Michael Feldman / CC BY 2.0 / bit. ly / 3Ff8ixS

Figure 6. An aldosterone producing adrenal adenoma from a patient with clinical Conn’ s syndrome. This photograph shows two contiguous slices of the adrenal gland with a cortical adenoma.

Box 5. A clinical trial assessing the optimal treatment of low renin hypertension

• REMASTER trial

• The 48-week trial aims to assess whether early spironolactone use is better for blood pressure and cardiometabolic health compared with standard blood pressure treatment for management of LREH.

• Participants living in Victoria are eligible if they are:— Treatment naïve and have a blood pressure greater than

140 / 90mmHg or any blood pressure on up to two blood pressure lowering medications, and have

— Low renin defined as a plasma renin concentration of less than

10mU / L.

• Further information for referring doctors is available in the REMASTER Trial pdf at hudson. org. au. Link: bit. ly / 47rUT1W

• The trial visits are at the Endocrine Hypertension Clinic, Department of Endocrinology, Monash Medical Centre, Clayton, Victoria.

Figure 7. Cushing’ s syndrome.