Abstract
Emerging evidence suggests that patients with low-renin hypertension (LRH) benefit from targeted treatment with mineralocorticoid receptor antagonists (MRA). With broader screening for primary aldosteronism (PA), clinicians are increasingly identifying patients with low renin levels who do not meet current diagnostic criteria for PA. In the absence of specific management guidelines, these patients are often treated as having primary hypertension. This study aimed to assess the prevalence, clinical characteristics, and real-world management of LRH in a tertiary endocrine hypertension clinic. We conducted a retrospective audit of patients evaluated between 2016 and 2021. PA was diagnosed based on saline suppression test (SST) results. LRH and normal renin hypertension (NRH) were classified using a direct renin concentration below or above 10mU/L, respectively. Among 409 eligible patients, 82 (20%) had LRH, 221 (54%) had PA, and 106 (26%) had NRH. Compared to NRH, patients with LRH were older despite a similar duration of hypertension, more likely to be female, and non-Caucasian. They also had a lower 24-h urinary aldosterone excretion compared to both PA and NRH. Automated office blood pressure, urinary sodium, and potassium excretion were similar across groups. Only 25 patients with LRH (31%) were prescribed an MRA; others were prescribed conventional antihypertensive agents and/or discharged to their primary care physician. LRH was present in one-fifth of patients referred to for endocrine hypertension assessment. Management was inconsistent, underscoring the need for evidence-based diagnostic and treatment strategies for this under-recognized subtype of hypertension.
Subject terms: Adrenal gland diseases, Hypertension
Introduction
Hypertension is the leading modifiable risk factor for cardiovascular morbidity and mortality globally. Primary aldosteronism (PA), characterized by inappropriate aldosterone production relative to an individual’s volume and sodium status, is increasingly recognized as an important contributor to hypertension, affecting up to 13% of people with hypertension in primary care and up to 30% in referral centers [1].
Many societies, including the Endocrine Society and European Society of Cardiology, advocate screening all hypertensive individuals with renin and aldosterone measurements to facilitate early detection of PA and initiation of targeted treatment, to reduce blood pressure and cardiovascular risk [2–4].
The diagnosis of PA typically relies on aldosterone suppression testing using intravenous saline, oral salt loading, or angiotensin-converting enzyme inhibitors, with a fixed aldosterone threshold to assess the adequacy of suppression [4]. However, these dichotomous criteria will exclude patients with low-renin hypertension (LRH), and may exclude those with mild autonomous aldosterone production, who do not meet the current diagnostic criteria for PA but may also benefit from targeted treatment with mineralocorticoid receptor (MR) antagonists (MRA) [5]. A meta-analysis of randomized clinical trials that included patients with LRH (PA excluded) showed that MRA were superior in lowering blood pressure compared to angiotensin converting enzyme inhibitors and angiotensin receptor blockers, and were similar in efficacy to epithelial sodium channel inhibitors (ENaCi) [6]. These findings suggest that many individuals with hypertension, low renin, and an aldosterone concentration below the diagnostic cutoff for PA may still benefit from MR-targeted therapy rather than being managed as having primary hypertension. A likely consequence of expanded PA screening is increased detection of LRH, providing an opportunity for earlier initiation of effective treatment.
Real-world data on how these individuals are currently managed in clinical practice are lacking. We therefore conducted this cohort study to: 1) quantify the proportion of patients referred to an Endocrine Hypertension clinic at a tertiary hospital who have LRH, 2) describe their clinical characteristics, and 3) assess their management in the absence of specific guidelines.
Methods
Study design
We performed a retrospective analysis of consecutive patients seen at the Endocrine Hypertension Clinic at Monash Health between its inception in 2016 and 2021. Since opening, the clinic has expanded its capacity to accommodate increasing referral demand over the audit period. Monash Health, the largest tertiary public health service in Victoria, Australia, receives referrals from primary care physicians and other specialists and serves a culturally and socioeconomically diverse population. Patients were included if they attended the clinic at least once and had both aldosterone and renin levels measured while not taking antihypertensive medications known to interfere with the renin-angiotensin-aldosterone system.
Saline suppression test and definitions for the subtype of hypertension
At Monash Health, patients with a positive screening ARR defined as >70 pmol/mU (25 ng/mU), measured off interfering antihypertensive medications, were referred for confirmatory testing with a saline suppression test (SST) (2 L of 0.9% saline over 4 h) [4]. Inadequate aldosterone suppression, consistent with a diagnosis of PA, was defined as a post-saline aldosterone concentration >140pmol/L (5.1 ng/dL) supine or >170pmol/L (6.1 ng/dL) seated [4, 7]. Patients who did not meet diagnostic criteria for PA were further classified based on their direct renin concentration (DRC): LRH was defined by a DRC <10mU/L, and normal-renin hypertension (NRH) was defined by a DRC ≥10mU/L.
For patients classified as having LRH, we collected data on their clinical management, including whether MRA was commenced and whether their care was referred to a primary care physician.
Clinical parameters
Ethnicity, cardio-metabolic co-morbidities, and antihypertensive medications were self-reported. Antihypertensives were quantified using the World Health Organization’s Defined Daily Dose index. Automated office blood pressure was measured in the seated position in triplicate, and the mean of the 2nd and 3rd measurement was calculated at baseline and 12 months from treatment initiation. Body mass index was calculated at the initial clinic visit as follows: weight in kilograms divided by height in meters squared.
Biochemistry
Plasma aldosterone and renin were measured at seven accredited laboratories, which all utilized the DiaSorin LIAISON® chemiluminescent immunoassays on the Liaison XL analyzer (DiaSorin, Saluggia, Italy). Clinic patients are routinely advised to have their pathology tests done in a seated position, approximately two hours after waking, with no change in their dietary salt intake.
For the aldosterone assay, the quoted between-run analytical coefficients of variation were 9.5% at 188 pmol/L and 5.6% at 798 pmol/L (1 ng/dL = 277 pmol/L). The DRC was reported in mU/L; the quoted between-run analytical coefficients of variation were 10.0% at 5.1 mU/L and 4.3% at 82.4 mU/L. Although there is no direct conversion factor available between DRC and plasma renin activity, 1 mU/L approximately is equal to 0.1 ng/ml/hour.
Serum lipids, glucose, insulin, creatinine, and electrolytes (sodium, potassium) were measured using standard automated assays.
Urine collection
Twenty-four-hour urine aldosterone, sodium, and potassium excretion were measured from a complete 24-h urine collection (acidified for preservation). Aldosterone was quantified by immunoassay.
Statistical methods
Data distribution was assessed using the Kolmogorov–Smirnov test and visual inspection of boxplots. Continuous variables were summarized as medians with interquartile ranges (25th, 75th percentiles). Group comparisons were performed using the Kruskal–Wallis test for continuous variables and the Chi-square test for categorical variables. A p-value of <0.05 was considered statistically significant. Post hoc comparisons were performed with a Bonferroni adjustment. All statistical analyses were conducted using IBM SPSS Statistics, version 28 (Armonk, NY, USA).
Ethics approval
This clinical audit was conducted in accordance with the NHMRC National Statement on Ethical Conduct in Human Research (2025) and the Declaration of Helsinki. It was exempt from Human Research Ethics Committee review, and all data were de-identified to maintain patient confidentiality.
Reporting
Findings are reported following the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) framework.
Results
Proportion of clinic patients with LRH
A total of 514 patients were seen at the Endocrine Hypertension Clinic between 2016 and 2021. Eighty-four patients had renin and aldosterone measured on interfering medications and were therefore excluded. One patient entered a randomized trial that is currently underway and was also excluded [8]. Out of the 409 eligible patients, 82 (20%) were classified as having LRH, 221 (54%) had PA, and 106 (26%) had NRH (Fig. 1). The proportion of patients seen with LRH per year varied from 11% to 31% (Fig. 2).
Fig. 1. The flow chart shows the patients eligible for the study and the reasons for exclusion.
The proportion of patients with primary aldosteronism, low-renin hypertension and normal-renin hypertension in the clinic is shown in percentages. N: number. *n = 13 with direct renin concentration >46.1mU/L.
Fig. 2. Annual clinic attendance and percentage of patients with low‑renin hypertension (2016–2021).
The figure displays the number of patients seen in the endocrine hypertension clinic each year from 2016 to 2021, along with the proportion diagnosed with low‑renin hypertension shown in percentages. PA primary aldosteronism, LRH low-renin hypertension, NRH normal-renin hypertension.
Saline suppression tests
Among those who underwent the seated SST (n = 172), the pre-saline serum potassium was lower in patients with PA compared to NRH (4.0 vs. 4.4 mmol/L, p < 0.05), but similar to that of patients with LRH (4.1 mmol/L) (Table 1). The median pre-saline aldosterone concentration was lower in patients with LRH compared to PA (292 pmol/L (10.5 ng/dL) vs. 464 pmol/L (16.7 ng/dL), p < 0.001) but similar to values for NRH (370 pmol/L). As expected, post-SST aldosterone concentration was lower in patients with LRH compared to PA (143 pmol/L (5.2 ng/dL) vs. 257 pmol/L (9.3 ng/dL), p < 0.001) but similar to patients with NRH (142 pmol/L (5.1 ng/dL)). A similar pattern was seen in patients who underwent a supine SST (n = 85) (Table 1).
Table 1.
Baseline characteristics of patients.
| Diagnosis | Overall p-value | |||
|---|---|---|---|---|
| LRH (N = 82) | NRH (N = 106) | PA (N = 221) | ||
| Age at study entry (years) | 55 (45, 65) | 46 (36, 58) *† | 53 (44, 59) | <0.001 |
| Sex N (%) female | 54 (66%)‡ | 51 (48%) | 121 (55%) | 0.051 |
| Duration of hypertension (years) | 2 (0,10) | 4 (1,11) | 4 (1,11) | 0.172 |
| Ethnicity? N (%) | ||||
| Caucasian | 46 (61%) | 72 (77%)§‡ | 129 (60%) | 0.152 |
| East Asian | 5 (7%) | 5 (5%) | 13 (6%) | |
| South Asian | 6 (8%) | 7 (8%) | 17 (8%) | |
| African | 7 (9%) | 4 (4%) | 15 (7%) | |
| Middle Eastern | 3 (4%) | 1 (1%) | 16 (8%) | |
| Polynesian | 1 (1%) | 2 (2%) | 11 (5%) | |
| Other | 7 (9%) | 2 (2%) | 13 6%) | |
| Aldosterone (pmol/L) | 314 (219, 500) | 368 (269, 516) | 452 (344, 641)§|| | <0.001 |
| Renin (mU/L) | 3.1 (2.0, 6.2) | 20.2 (13.5, 29.4)*† | 3.7 (2.0, 6.1) | <0.001 |
| ARR (pmol/mU) | 105 (52, 201) | 20 (12, 27)*† | 123 (81, 213) | <0.001 |
| eGFR (mL/min) | 90 (78, 90) | 90 (77, 90) | 90 (82, 90) | 0.853 |
| Sodium (mmol/L) | 141 (139, 142) | 141 (139, 142) | 141 (139, 142) | 0.679 |
| Potassium (mmol/L) | 4.2 (4.0, 4.5) | 4.3 (4.0, 4.6) | 4.1 (3.8, 4.3)†# | <0.001 |
| Bicarbonate (mmol/L) | 27 (25, 29) | 27 (26, 28) | 27 (26, 29) | 0.131 |
| Creatinine (umol/L) | 65 (55, 81)* | 79 (65, 88) | 70 (61, 84) | <0.001 |
| Urine excretion | N = 42 | N = 64 | N = 113 | |
| Spot urine Albumin: creatinine ratio (mg/mmol) | 1.1 (0.8, 2.9) | 1.2 (0.6, 5.6) | 1.6 (0.9, 3.6) | 0.525 |
| Sodium excretion (mmol/day) | 129 (95, 201) | 141 (98, 200) | 130 (97, 207) | 0.896 |
| Potassium excretion (mmol/day) | 61 (48, 84) | 73 (54, 90) | 72 (57, 98) | 0.162 |
| Aldosterone excretion (nmol/day) | 22 (14, 28)‡|| | 29 (21, 43) | 33 (22, 46) | <0.001 |
| Supine saline suppression test | N = 3 | N = 82 | ||
| Pre: Potassium (mmol/L) | 4.2 (3.9,4.6) | 3.9 (3.8 4.2) | 0.378 | |
| Pre: Aldosterone (pmol/L) | 170 (160, 211) | 408 (282, 538) | 0.012 | |
| Pre: Cortisol (nmol/L) | 181 (175, 223) | 254 (190, 326) | 0.215 | |
| Pre: Renin (mU/L) | 2.1 (1.0, 2.6) | 2.9 (1.3, 5.7) | 0.385 | |
| Pre: ARR (supine, pmol/mU) | 76 (55, 164) | 148 (71, 275) | 0.552 | |
| Post: Potassium (mmol/L) | 4.2 (4.2, 4.4) | 3.8 (3.6, 4.1) | 0.035 | |
| Post: Aldosterone (pmol/L) | 107 (100, 112) | 230 (171, 333) | 0.004 | |
| Post: Cortisol (nmol/L) | 105 (89, 143) | 166 (129, 229) | 0.156 | |
| Post: Renin (mU/L) | 1.3 (0.5, 2.1) | 1.8 (0.8, 3.0) | 0.541 | |
| Post: ARR (pmol/mU) | 64 (38, 89) | 142 (79, 264) | 0.118 | |
| Seated saline suppression test | N = 31 | N = 6 | N = 135 | |
| Pre: Potassium (mmol/L) | 4.1 (3.9, 4.2) | 4.4 (4.2, 4.5)§ | 4.0 (3.8, 4.2) | 0.021 |
| Pre: Aldosterone (pmol/L) | 293 (239, 424)|| | 370 (290, 480) | 464 (351, 668) | <0.001 |
| Pre: Cortisol (nmol/L) | 226 (176, 347) | 301 (218, 389) | 282 (221, 338) | 0.183 |
| Pre: Renin (mU/L) | 3.5 (1.8, 6.7) | 13.5 (9.1, 25.0)ठ| 5.2 (2.2, 9.6) | 0.005 |
| Pre: ARR (pmol/mU) | 75 (48, 167) | 29 (16, 41) ठ| 87 (49, 155) | 0.004 |
| Post: Aldosterone (pmol/L) | 143 (123, 164) | 142 (117, 162) | 257 (220, 370)†|| | <0.001 |
| Post: Potassium (mmol/L) | 3.9 (3.8, 4.2) | 4.4 (4.0, 4.6) | 3.9 (3.7, 4.2) | 0.062 |
| Post: Cortisol (nmol/L) | 129 (100, 185) | 159 (121, 234) | 173 (128, 218) | 0.128 |
| Post: Renin (mU/L) | 1.9 (1.2, 3.9)‡ | 6.5 (5.0, 12.8) | 3.0 (1.8, 5.7) | 0.012 |
| Post: ARR (pmol/mU) | 75 (39, 110) | 21 (13, 27)ठ| 78 (48, 142) | 0.001 |
*NRH vs. LRH p < 0.001, †NRH vs. PA p < 0.001, ‡NRH vs. LRH p < 0.05, § NRH vs PA p < 0.05, ||LRH vs. PA p < 0.001 and #LRH vs. PA p < 0.05.
ARR aldosterone-to-renin ratio, eGFR estimated glomerular filtration rate, LRH low-renin hypertension, N number, NRH normal-renin hypertension, PA primary aldosteronism.
Clinical and biochemical characteristics
Patients with NRH were younger compared to those with PA and LRH (46 years vs. 53 years and 55 years, p < 0.001). However, the duration of hypertension was similar across the three groups (NRH and PA: 4 years, and LRH: 2 years, p = 0.172) (Table 1).
In the LRH group, a higher proportion were female compared to the NRH group (66% vs. 48%, p < 0.05), and fewer were Caucasian (61% vs. 77%, p < 0.05). The remainder of patients with LRH were East Asian (7%), South Asian (8%), African (9%), Middle Eastern (4%), or Polynesian (1%).
In patients with PA, median serum potassium was somewhat lower compared to those with NRH and LRH (4.1 mmol/L vs. 4.3 and 4.2 mmol/L, p < 0.05), but urinary potassium excretion was comparable across groups: 72 mmol/day vs. 73 mmol/day and 61 mmol/day, p = 0.162). Despite a similar median aldosterone concentration for LRH and NRH, the 24-h urinary aldosterone excretion was lower in LRH compared to NRH (22 nmol/day vs. 29 nmol/day, p < 0.05). Median serum sodium and urinary sodium excretion were also similar across all groups.
Serum creatine was lower in those with LRH compared to NRH (65 umol/L vs. 79 umol/L, p < 0.001) but similar to PA (70 umol/L). When stratified by sex, this difference persisted only in females (p = 0.009), not in males (p = 1.000) (Supplementary Figure 1). Spot urine albumin-creatinine ratio was similar across groups (LRH: 1.1, NRH: 1.2, and PA: 1.6 mg/mmol, p = 0.525).
Baseline blood pressure, cardiometabolic characteristics, and antihypertensive use
Median automated office blood pressure in patients with LRH (SBP: 140 mmHg and DBP: 89 mmHg) was similar to that of those with NRH (Table 2). However, patients with NRH had a lower SBP and DBP compared to those with PA (p < 0.001). Anti-hypertensive medication use, expressed as WHO-defined daily dose (DDD), was similar across all groups (LRH: 1.3, NRH: 1.1, and PA: 1.1).
Table 2.
Baseline blood pressure, antihypertensive use, and cardiometabolic characteristics.
| Diagnosis | Overall p-value | |||
|---|---|---|---|---|
| LRH N = 82 | NRH N = 106 | PA N = 221 | ||
| Stroke N (%) | 6 (7%) | 9 (9%) | 8 (4%) | 0.153 |
| Ischemic heart disease N (%) | 3 (4%) | 6 (6%) | 3 (1%) | 0.089 |
| Arrhythmia N (%) | 5 (6%) | 6 (6%) | 8 (4%) | 0.559 |
| Chronic kidney disease N (%) | 3 (4%) | 9 (9%) | 13 (6%) | 0.382 |
| Dyslipidemia N (%) | 30 (37%) | 32 (30%) | 67 (30%) | 0.546 |
| Diabetes N (%) | 11 (13%) | 15 (14%) | 28 (13%) | 0.932 |
| Obstructive sleep apnea N (%) | 10 (12%) | 12 (11%) | 32 (15%) | 0.700 |
| Heart failure N (%) | 2 (2%) | 0 (0%) | 2 (1%) | 0.239 |
| Number of current antihypertensives used | 1 (1, 2) | 1 (1, 2) | 1 (1, 2) | 0.860 |
| Defined daily dose of baseline antihypertensives (other than MRA) | 1.0 (0.2, 3.0) | 1.1 (0.4, 3.0) | 1.0 (0.0, 3.0) | 0.801 |
| Defined daily dose of MRA at baseline | 0.7 (0.3, 1.3)* | 0.0 (0.0, 0.3) | 0.0 (0.0, 0.7) | 0.028 |
| Total defined daily dose of antihypertensives at baseline | 1.3 (0.4,3.0) | 1.1 (0.4, 3.0) | 1.1 (0.3, 3.1) | 0.866 |
| Systolic blood pressure (mmHg) | 140 (124, 155) | 135 (128, 148)† | 145 (133, 158) | <0.001 |
| Diastolic blood pressure (mmHg) | 89 (82, 95) | 85 (78, 95)† | 91 (84, 99) | <0.001 |
| BMI (kg/m2) | 28.7 (25.0, 33.9) | 29.8 (26.4, 36.4) | 28.8 (25.4, 33.0) | 0.083 |
| Metabolic profile | N = 52 | N = 78 | N = 99 | |
| Glucose (fasting, mmol/L) | 5.2 (5.0, 6.0) | 5.5 (5.0, 6.2) | 5.4 (5.0, 5.9) | 0.748 |
| Insulin (fasting, mU/L) | 11.0 (6.7, 17.6) | 13.0 (7.0, 21.6)‡ | 9.0 (5.0, 12.4) | 0.048 |
| Total cholesterol (fasting, mmol/L) | 5.2 (4.5, 6.1) | 4.8 (4.0, 5.8) | 5.1 (4.7, 5.8) | 0.128 |
| LDL (fasting, mmol/L) | 3.2 (2.6, 3.8) | 2.7 (2.2, 3.6)‡ | 3.1 (2.6, 3.8) | 0.016 |
| HDL (fasting, mmol/L) | 1.4 (1.2, 1.7) | 1.3 (1.1, 1.6) | 1.3 (0.9, 1.7) | 0.504 |
| Triglyceride (fasting, mmol/L) | 1.4 (1.1, 1.8) | 1.3 (0.9, 2.0) | 1.3 (0.9, 1.6) | 0.508 |
BMI body mass index, HDL high-density lipoprotein; low-density lipoprotein, LRH low-renin hypertension, MRA mineralocorticoid receptor antagonists, N number, NRH normal-renin hypertension; PA: primary aldosteronism.
*LRH vs. NRH p < 0.05, †NRH vs PA p < 0.001 and ‡ NRH vs PA p < 0.05.
Fasting insulin and low-density lipoprotein (LDL) cholesterol levels were similar in patients with LRH (11.0 mU/L and 3.2 mmol/L, respectively) when compared to those with NRH and PA. Fasting total cholesterol, high-density lipoprotein (HDL), triglyceride, glucose, and body mass index were similar for all groups.
Among patients with LRH, 37% had concomitant dyslipidemia. Smaller proportions of patients with LRH had diabetes (13%), obstructive sleep apnea (12%), stroke (7%), ischemic heart disease (4%), heart failure (3%), arrhythmia (6%), and chronic kidney disease (4%). The prevalence of co-morbidities was comparable across the groups.
Management of patients with low-renin hypertension
Of the 82 patients with LRH, 25 (31%) were prescribed MRA, 4 (5%) angiotensin converting inhibitors or angiotensin II receptor blockers, 2 (2%) diuretics (non-potassium sparing), 5 (6%) beta blockers, 10 (11%) calcium channel blockers, 3 (4%) alpha-1 blockers (prazosin), 5 (6%) alpha-2/imidazoline receptor agonist (moxonidine) and 1 (1%) direct vasodilator (hydralazine). The remainder were not commenced on anti-hypertensives. Approximately half of the patients (n = 40, 49%) were discharged to a primary physician for management of their hypertension.
Median 12-month automated office blood pressure was 130/79 mmHg in the LRH group (n = 33). There were no significant differences between groups in terms of 12-month blood pressure (both absolute and change from baseline) or DDD of antihypertensives (Table 3). Due to small sample sizes, blood pressure outcomes within the LRH group were not compared across different antihypertensive drug classes.
Table 3.
Automated office blood pressure and anti-hypertensive use at 12 months follow-up.
| Diagnosis | Overall p-value | |||
|---|---|---|---|---|
| LRH | NRH | PA | ||
| Automated office blood pressure | N = 33 | N = 7 | N = 183 | |
| SBP (mmHg) | 130 (123, 134) | 125 (115, 136) | 130 (123, 137) | 0.530 |
| DBP (mmHg) | 79 (76, 86) | 85 (75, 90) | 85 (78, 90) | 0.056 |
| Change in SBP (mmHg) | -13 (-26, -5) | -19 (-27, 5) | -17 (-27, -1) | 0.780 |
| Change in DBP (mmHg) | -13 (-18, -4) | -10 (-11, -4) | -7 (-15, 1) | 0.090 |
| Anti-hypertensive use | N = 25 | N = 3 | N = 140 | |
| DDD of antihypertensives (other than MRA) | 0.3 (0.0, 2.9) | N/A | 0.0 (0.0, 1.0) | 0.119 |
| DDD of MRA | 1.3 (0.7, 1.9) | N/A | 1.3 (0.7, 1.3) | 0.740 |
| Total DDD of antihypertensives | 1.8 (0.7, 4.7) | N/A | 1.4 (1.0, 2.7) | 0.650 |
DBP diastolic blood pressure, DDD defined daily dose, LRH low-renin hypertension, MRA mineralocorticoid receptor antagonists, N number, NRH normal-renin hypertension, PA primary aldosteronism, SBP systolic blood pressure.
Discussion
This study demonstrates that a significant proportion of patients referred to a tertiary endocrine hypertension clinic have low renin levels but do not meet the current biochemical criteria for PA. Concerningly, only one-third of these patients received targeted treatment despite growing evidence supporting the efficacy of MRA or ENaCi for treating LRH [6, 9–12]. The variability in clinical management likely reflects the lack of clear diagnostic and therapeutic guidelines for LRH, resulting in these patients often being managed similarly to those with primary hypertension.
In our cohort of patients seen at a specialized clinic, 20% were found to have LRH. This prevalence is comparable to findings in other populations. In a large study of 1267 hypertensive patients referred to a specialized center in China, 26% of patients had LRH, defined as a plasma renin activity <1 ng/ml/hour ( ~ DRC concentration ≤10 mU/L) and not meeting the criteria for PA [13]. This is consistent when dynamic testing is used to define LRH; in the HyperPath Consortium, a multisite study aimed at investigating the pathophysiology of hypertension in tertiary centers in USA and France, 19% of participants had LRH, defined by a stimulated plasma renin activity ≤2.4 ng/ml/hour ( ~ DRC ≤ 24 mU/L) after low salt diet and upright posture [14]. Interestingly, the prevalence of LRH is similar even in primary care, suggesting a more widespread and under-recognized clinical issue. In a prospective study of treatment-naïve hypertensive patients in primary care, 26% were found to have LRH [15]. This highlights the emerging challenge of managing a substantial subgroup of hypertensive patients for whom standard treatment guidelines may not apply.
The clinical and biochemical characteristics of patients with LRH in this study are similar to those reported previously: older age, a higher proportion of females, lower representation of Caucasian people, and lower aldosterone concentrations compared to those with NRH [15, 16]. Although not statistically significant, in this study, there was a trend toward higher proportions of patients identifying as Asian or African in the LRH group (24% vs. 17%), warranting further exploration in larger cohorts. These characteristics may be clues to the underlying pathophysiology of LRH, such as early/emerging aldosterone autonomy due to an age-related accumulation of aldosterone-producing adrenal cell clusters, or increased salt sensitivity in females and individuals of African-Caribbean or Asian background [17, 18]. Although a common cause of low renin and low aldosterone is high dietary salt intake, median sodium excretion, which is reflective of sodium intake, was similar for all groups. However, interpretation of this is limited as a 24-hour measurement provides a snapshot of current sodium intake and does not represent long-term exposure. Additionally, the power to detect differences may be reduced due to missing data (approximately 50% in each group did not have a 24-hour urine collection) and the potential inaccuracy of unsupervised outpatient collections.
An interesting finding was that female patients with LRH had lower serum creatinine compared with those with NRH. The underlying reason is unclear, as there were no differences in body mass index or reported cardiorenal disease between groups. Potential explanations include lower muscle mass due to differences in body composition despite similar body mass index, particularly given the older age of the LRH group. Alternatively, this finding may reflect glomerular hyperfiltration in LRH, analogous to that observed in PA, whereby intravascular volume expansion and alterations in glomerular hemodynamics (afferent arteriolar vasodilation and/or efferent arteriolar vasoconstriction) lead to artificially lower serum creatinine and inflated eGFR [19, 20]. No differences in serum creatinine were observed among male patients. These finding warrants further investigation in larger cohorts incorporating cystatin C measurements.
The strengths of this study include its real-world evaluation of a large, well-characterized cohort from a tertiary endocrine hypertension clinic, capturing detailed clinical, biochemical, and management data.
However, this study has several limitations. First, the classification of LRH and NRH was based on a dichotomous DRC threshold of 10 mU/L, selected based on prior evidence showing maximal blood pressure-lowering response to MRA in patients with renin concentration <9.4 mU/L [21]. However, this binary threshold may oversimplify a continuum, as demonstrated by the PATHWAY-2 trial. In this randomized clinic trial of add-on therapy for participants with resistant hypertension, an inverse relationship between renin concentration and blood pressure response to spironolactone was observed [10]. Second, not all patients in the clinic underwent medication adjustment or SST, often due to comorbidities or patient preference. There was also a change in the local SST protocol from a supine to a seated position, with corresponding post-SST aldosterone thresholds of 140 and 170 pmol/L, respectively, to improve the sensitivity of PA diagnosis. However, this change may have occurred at the expense of specificity, and led some patients with mild PA to be diagnosed as having LRH, thus over-estimating the prevalence of LRH [22]. These factors may have led to over- or under-estimation of LRH prevalence. Third, due to extensive engagement with primary care practitioners within the referral catchment and increased uptake of PA screening [23], a relatively high proportion of patients in this cohort had a milder PA phenotype. Consequently, these findings may not be generalisable to an unselected hypertensive population or to other tertiary referral centres without similar primary care screening practices. Finally, missing data on urinary excretion may have limited our power to detect differences in urinary sodium excretion between groups and differences in treatment efficacy between hypertension groups and between drug classes could not be adequately assessed, as only a small number of patients with LRH and NRH were followed up in the clinic. Future work should evaluate whether some or all patients with LRH experience improvements in blood pressure, potassium, and renin profiles when treated with MRA/ENaCi, and whether this translates into reduced cardiovascular risk compared to those managed with conventional antihypertensive regimens.
This retrospective study highlights that a substantial proportion of patients referred to a tertiary hypertension clinic have LRH, which falls outside current diagnostic thresholds for PA. Clinical management in this group varies widely, reflecting the lack of specific guidelines. As more hypertension guidelines advocate for PA screening [2–4], the number of people identified to have hypertension and low renin is expected to rise. With increasing detection of LRH and emerging evidence for using MRA or ENaCi to treat LRH, there is an urgent need for multicenter prospective studies to evaluate blood pressure and cardiovascular outcomes in patients with LRH treated with MR- and ENaC-targeted therapies, compared with conventional antihypertensives, to better inform future hypertension guidelines.
Summary
What is known about this topic?
Renin and aldosterone measurements are increasingly being used in the diagnostic work-up of individuals with hypertension, enabling earlier detection of primary aldosteronism (PA), which has well-established treatment pathways.
However, an anticipated by-product of this expanded screening is the growing recognition of people with low-renin hypertension who have normal or subthreshold aldosterone levels that do not meet diagnostic criteria for PA.
A current gap in hypertension guidelines is that low-renin hypertension is not specifically addressed, despite growing evidence that people with low-renin (even without PA) may benefit from mineralocorticoid receptor/epithelial sodium channel–targeted therapy.
What is new?
This study provides detailed real-world evaluations of low-renin hypertension in a tertiary endocrine hypertension clinic, identifying that 20% of patients being investigated for PA fall into this category.
This study reveals varied management of low-renin hypertension, with only one-third receiving mineralocorticoid receptor antagonists, despite emerging evidence supporting the use of this targeted treatment.
It highlights the need for further research in the optimal management of low-renin hypertension to inform future clinical practice guidelines.
Supplementary information
Acknowledgements
We would like to acknowledge the contributions of clinicians, nurses, and administrative staff working in the Endocrine Hypertension Clinic and Francis Slattery for assisting with data collection.
Author contributions
The authors confirm their contribution to the paper as follows: study conception and design: SSS, CN, RL, and JY; data collection: CN, MWC, and SSS; statistical analysis and manuscript drafting: SSS; manuscript editing: SSS, CN, MWC, MJY, PJF, RL, and JY. All authors reviewed the results and approved the final version of the manuscript.
Funding
S.S.S. is supported by a National Health and Medical Research Council postgraduate scholarship (APP2013946). M.J.Y. is supported by the Alice Baker and Eleanor Shaw Gender Equity Fellowship, Baker Heart and Diabetes Institute, Australian Research Council (DP230103229), and National Heart Foundation of Australia (106729). J.Y. is supported by project funding from a National Health and Medical Research Council investigator grant (APP1194576). The Hudson Institute of Research and the Baker Heart and Diabetes Institute are supported by the Victorian Government’s Operational Infrastructure Scheme. Open Access funding enabled and organized by CAUL and its Member Institutions.
Data availability
Data is available from the corresponding author upon reasonable request.
Competing interests
The authors have no conflicts of interest to declare. Data availability for datasets generated during and/or analyzed during the current study is not publicly available but can be made available from the corresponding author upon reasonable request.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41371-026-01148-3.
References
- 1.Kayser SC, Dekkers T, Groenewoud HJ, van der Wilt GJ, Carel Bakx J, van der Wel MC, et al. Study heterogeneity and estimation of prevalence of primary aldosteronism: a systematic review and meta-regression analysis. J Clin Endocrinol Metab. 2016;101:2826–35. [DOI] [PubMed] [Google Scholar]
- 2.Naruse M, Katabami T, Shibata H, Sone M, Takahashi K, Tanabe A, et al. Japan endocrine society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021. Endocr J. 2022;69:327–59. [DOI] [PubMed] [Google Scholar]
- 3.McEvoy JW, McCarthy CP, Bruno RM, Brouwers S, Canavan MD, Ceconi C, et al. 2024 ESC guidelines for the management of elevated blood pressure and hypertension. Eur Heart J. 2024;45:3912–4018. [DOI] [PubMed] [Google Scholar]
- 4.Adler GK, Stowasser M, Correa RR, Khan N, Kline G, McGowan MJ, et al. Primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2025;110:2453–95. [DOI] [PubMed] [Google Scholar]
- 5.Brown JM, Siddiqui M, Calhoun DA, Carey RM, Hopkins PN, Williams GH, et al. The unrecognized prevalence of primary aldosteronism: a cross-sectional study. Ann Intern Med. 2020;173:10–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Shah SS, Zhang J, Gwini SM, Young MJ, Fuller PJ, Yang J. Efficacy and safety of mineralocorticoid receptor antagonists for the treatment of low-renin hypertension: a systematic review and meta-analysis. J Hum Hypertens. 2024;38:383–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Thuzar M, Young K, Ahmed AH, Ward G, Wolley M, Guo Z, et al. Diagnosis of primary aldosteronism by seated saline suppression test-variability between immunoassay and HPLC-MS/MS. J Clin Endocrinol Metab. 2020;105:dgz150. [DOI] [PubMed] [Google Scholar]
- 8.Shah SS, Gwini SM, Stowasser M, Reid CM, Young MJ, Fuller PJ, et al. A Randomized trial assessing efficacy and safety of mineralocorticoid receptor antagonist therapy compared to standard antihypertensive therapy in hypErtension with low renin (REMASTER): rationale and study design. J Hum Hypertens. 2024;38:663–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ori Y, Chagnac A, Korzets A, Zingerman B, Herman-Edelstein M, Bergman M, et al. Regression of left ventricular hypertrophy in patients with primary aldosteronism/low-renin hypertension on low-dose spironolactone. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2013;28:1787–93. [DOI] [PubMed] [Google Scholar]
- 10.Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes GT, et al. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. 2018;6:464–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Mansur A, Vaidya A, Turchin A. Using renin activity to guide mineralocorticoid receptor antagonist therapy in patients with low renin and hypertension. Am J Hypertens. 2023;36:455–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Tsai CH, Brown JM, Parisien-La Salle S, Newman AJ, Wu VC, Lin YH, et al. ACE inhibition to distinguish low-renin hypertension from primary aldosteronism. Hypertension. 2025;82:1046–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Luo Q, Li N, Wang M, Yao X, Heizhati M, Zhang D, et al. Mild primary aldosteronism (PA) followed by overt PA are possibly the most common forms of low renin hypertension: a single-center retrospective study. J Hum Hypertens. 2020;34:633–40. [DOI] [PubMed] [Google Scholar]
- 14.Vaidya A, Forman JP, Hopkins PN, Seely EW, Williams JS. 25-Hydroxyvitamin D is associated with plasma renin activity and the pressor response to dietary sodium intake in caucasians. J Renin Angiotensin Aldosterone Syst. 2011;12:311–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Shah SS, Libianto R, Gwini SM, Rusell G, Young MJ, Fuller PJ, et al. Prevalence and characteristics of low-renin hypertension in a primary care population. J Endocr Soc. 2024;8:bvae113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Rifkin DE, Khaki AR, Jenny NS, McClelland RL, Budoff M, Watson K, et al. Association of renin and aldosterone with ethnicity and blood pressure: the multi-ethnic study of atherosclerosis. Am J Hypertens. 2014;27:801–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Omata K, Anand SK, Hovelson DH, Liu CJ, Yamazaki Y, Nakamura Y, et al. Aldosterone-producing cell clusters frequently harbor somatic mutations and accumulate with age in normal adrenals. J Endocr Soc. 2017;1:787–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Masenga SK, Wandira N, Cattivelli-Murdoch G, Saleem M, Beasley H, Hinton A Jr., et al. Salt sensitivity of blood pressure: mechanisms and sex-specific differences. Nat Rev Cardiol. 2025;22:611–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Kuo CC, Wu VC, Tsai CW, Wu KD. Taiwan primary aldosteronism investigation study G. relative kidney hyperfiltration in primary aldosteronism: a meta-analysis. J Renin Angiotensin Aldosterone Syst. 2011;12:113–22. [DOI] [PubMed] [Google Scholar]
- 20.Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol. 2012;8:293–300. [DOI] [PubMed] [Google Scholar]
- 21.Weinberger MH, White WB, Ruilope LM, MacDonald TM, Davidson RC, Roniker B, et al. Effects of eplerenone versus losartan in patients with low-renin hypertension. Am Heart J. 2005;150:426–33. [DOI] [PubMed] [Google Scholar]
- 22.Ahmed AH, Cowley D, Wolley M, Gordon RD, Xu S, Taylor PJ, et al. Seated saline suppression testing for the diagnosis of primary aldosteronism: a preliminary study. J Clin Endocrinol Metab. 2014;99:2745–53. [DOI] [PubMed] [Google Scholar]
- 23.Libianto R, Russell GM, Stowasser M, Gwini SM, Nuttall P, Shen J, et al. Detecting primary aldosteronism in Australian primary care: a prospective study. Med J Aust. 2022;216:408–12. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data is available from the corresponding author upon reasonable request.