Version July 2025
INTRODUCTION —
Assessment of the renin-angiotensin-aldosterone system has an important role in clinical practice, particularly in the evaluation of patients with hypertension. The most common indication is evaluating for primary aldosteronism, which is present in as many as 5 to 20 percent of adults with hypertension and often lacks hypokalemia as a clinical clue [1].
In addition, the renin-angiotensin-aldosterone system is often assessed in patients with:
●Hypokalemia (to evaluate for hyperaldosteronism or other forms of real or apparent mineralocorticoid excess)
●Hyperkalemia (to evaluate for hypoaldosteronism)
●Adrenal insufficiency (to distinguish primary from central [ie, secondary or tertiary])
This topic will review the use of renin and aldosterone measurements. The specific approaches to evaluating patients with potential disorders of aldosterone production are reviewed separately.
●(See "Diagnosis of primary aldosteronism".)
●(See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)
●(See "Causes and evaluation of hyperkalemia in adults".)
●(See "Determining the etiology of adrenal insufficiency in adults".)
●(See "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)
RENIN
Testing options — Renin can be measured in terms of its enzymatic activity (plasma renin activity [PRA]), or its mass (direct renin concentration [DRC]). (See "Diagnosis of primary aldosteronism", section on 'Initial testing'.)
Plasma renin activity — Renin does not directly affect blood pressure but does so indirectly through generating angiotensin. PRA is measured by incubating plasma at 37°C without addition of substrate (angiotensinogen); the assay instead relies on endogenous angiotensinogen in the plasma sample [2]. Renin cleaves angiotensinogen to produce a decapeptide, angiotensin I, which is measured by radioimmunoassay or liquid chromatography-tandem mass spectrometry (LC-MS/MS) [3,4]. (See 'Result interpretation' below.)
PRA is expressed as the amount of angiotensin I generated per unit of time. The recommended incubation time is typically 90 minutes. However, incubation time should be extended up to 18 hours for samples with very low activity (ie, <1 ng/mL per hour) to permit enough angiotensin I generation to ensure assay reproducibility at the lower end of the scale [5]. Subtracting the amount of preformed angiotensin I in a control aliquot incubated at 4°C is suggested, but this may reduce the reproducibility of the test [5].
Direct renin concentration — The plasma concentration of the active (cleaved) form of renin can be measured by radioimmunoassay but is usually measured by automated immunometric assay [6]. Automated immunometric assays for measuring active renin have been adopted in many laboratories because they are faster and more convenient than PRA or renin concentration radioimmunoassays.
Assay selection — PRA is more time-consuming but, if available, has some advantages over DRC:
●PRA, unlike DRC, accounts for endogenous renin substrate (angiotensinogen) levels and therefore better reflects angiotensin II concentrations. This is important in the context of higher circulating estrogens (eg, pregnancy, exogenous estrogens), which stimulate production of renin substrate. The resulting rise in angiotensin II (via angiotensin I) suppresses renal production of renin through a negative feedback mechanism, and DRC falls [6]. In contrast, PRA remains relatively constant. As a result, when women receiving exogenous estrogens are screened for primary aldosteronism with aldosterone/renin ratio testing, false-positive results can occur when renin is measured as DRC, but not when it is measured as PRA [7,8]. A sustained effect of the preovulatory surge in estradiol is also thought to underlie the reported occurrence of false-positive aldosterone/renin ratios using DRC (but not PRA) during the luteal phase of the menstrual cycle [9]. (See 'Key considerations for testing' below.)
●Concerns also exist about the reliability of automated immunometric, chemiluminescent methods of measuring DRC, particularly at the lower end of the clinical range. The lower end of this range is critical when the aldosterone/renin ratio is used to screen for primary aldosteronism. The units of the aldosterone/renin ratio also differ if PRA versus DRC assays are used. (See "Diagnosis of primary aldosteronism", section on 'PAC to PRA ratio'.)
Key considerations for testing — Nonpathologic factors can affect renin measurements [10,11]. These variables inform the choice of renin assay and timing of sample collection.
●Patient-specific factors
•Dietary sodium – Prior to renin measurement, patients should have unrestricted dietary sodium intake (eg, 2500 to 4500 mg daily). Renin may be stimulated by dietary sodium restriction and suppressed by consumption of a high-sodium diet.
•Kidney function – As kidney function declines with age, renin levels gradually fall. In chronic kidney disease, renin-producing capacity is reduced, and sodium retention further contributes to renin suppression.
•Sex, menstrual phase, and pregnancy – Initial renin measurement can generally be performed during any phase of the menstrual cycle. If initial results are equivocal, repeat sample collection ideally should be performed during menses or the follicular phase of the menstrual cycle. Menstruating women have lower renin levels during menses and the follicular (but not luteal) phases of the menstrual cycle when compared with age-matched men [9]. Renin levels are higher in the luteal phase of the menstrual cycle and during pregnancy [12,13], in part due to a compensatory response to the mineralocorticoid antagonist activity of progesterone. The rise in PRA during the luteal phase appears greater than that in DRC, probably because the late follicular surge in estradiol leads to a sustained rise in renin substrate (angiotensinogen) that persists into the luteal phase [9].
•Medication use – Many medications affect renin levels. However, for initial testing for primary aldosteronism, renin measurement does not require withholding potentially interfering medications. Although withholding such medications was once recommended, this guidance has changed to facilitate testing given the underdiagnosis of primary aldosteronism. Nonetheless, concurrent medications should be considered when interpreting renin levels. If initial testing results are equivocal or medication interference is suspected, potentially interfering agents typically should be withheld for two to four weeks prior to repeat renin measurement when possible, and diuretics (eg, spironolactone) should be withheld for six weeks prior to testing. (See "Diagnosis of primary aldosteronism", section on 'Interfering drugs'.)
For renin measurement for other indications, the approach to withholding medications prior to testing varies with the indication for measurement, the safety of withholding treatment, and the specific medication.
-Medications that increase renin include diuretics (eg, spironolactone), dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.
-Medications that decrease renin by reducing beta-sympathetic stimulation of renin release include beta blockers, clonidine, and alpha-methyldopa. Nonsteroidal antiinflammatory agents (NSAIDs) decrease renin by promoting sodium retention and inhibiting renal prostaglandin production.
-Direct renin inhibitors lower PRA but raise DRC.
If alternative hypertensive therapy is needed while interfering medications are withheld, verapamil slow-release and alpha blockers (eg, prazosin, moxonidine) minimally affect renin measurements and may be used [11,14,15].
●Sample collection – Blood samples for renin measurement should be collected in the morning while the patient is upright and seated. Samples should not be drawn into cold tubes. Blood samples should be collected, transported, and processed at room temperature without chilling or icing. Plasma can then be frozen and stored at -80°C before assaying [16].
•Time of day – Renin levels show a diurnal rhythm; they are highest in the early morning upon awakening and decrease during the day [17].
•Posture – With assumption of upright posture, blood translocates into the lower limbs. Kidney perfusion pressure falls and sympathetic output increases, leading to increased renin release from juxtaglomerular cells [18].
ALDOSTERONE
Testing options — Aldosterone production may be assessed either by measuring serum (or plasma) aldosterone or urinary aldosterone secretion. Serum aldosterone is more commonly measured to avoid the inconvenience of 24-hour urine collection, which is required for measuring urinary aldosterone secretion.
Serum aldosterone — Serum aldosterone can be measured by radioimmunoassay [19]. The assay requires a high-affinity, highly specific antibody because aldosterone concentrations in serum are less than 1 percent of cortisol concentrations. In most laboratories, this has been replaced by faster, more convenient methods of directly measuring aldosterone using chemiluminescent immunoassay (CLIA) techniques and automated machinery [20,21].
Concerns with the CLIAs include:
●Potential for false-negative suppression tests. In one analysis, aldosterone levels were below the assay's limit of detection for over one-half the samples collected from healthy participants and for nearly one-half of those from patients with primary hypertension (formerly called "essential" hypertension) [22].
●Nonspecific interference, possibly due to the brevity of the "wash" immediately prior to chemiluminescence. This interference leads to an unacceptably high "blank" value in patients with primary adrenal insufficiency or those who have undergone bilateral adrenalectomy.
●Weaknesses of the assay system. The system is calibrated by only a two-point recalibration against a stored master curve, and the two calibrators are reconstituted lyophilized aldosterone. Inclusion of blanks using plasma from patients with primary adrenal insufficiency or those who have undergone bilateral adrenalectomy, as well as calibration using plasma pools from persons with known low, medium, or high values, would permit valuable, ongoing evaluation of the system.
Highly accurate and reproducible methods of measuring aldosterone using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) have been developed and are now in clinical use [23,24]. The incorporation of semiautomated technology has meant that these methods can generate results rapidly and with relatively high throughput. Because of their greater accuracy, a growing number of institutions are adopting this technology in place of immunoassays. A multicenter comparison of LC-MS/MS versus immunoassay-measured aldosterone levels demonstrated a tendency for immunoassay to substantially overestimate aldosterone concentrations, especially at the lower end of the range, leading to frequent false-positive results on saline suppression testing [4].
Urinary aldosterone excretion — Measuring urinary aldosterone secretion requires 24-hour urine collection. Aldosterone, usually in the form of its 18-glucuronide, can be measured by immunoassay or LC-MS/MS.
Key considerations for testing
●Patient-specific factors – Prior to aldosterone measurement, hypokalemia should be corrected with potassium chloride (KCl) supplements, and patients should follow a diet with unrestricted sodium intake (eg, 2500 to 4500 mg daily).
•Volume status – Serum aldosterone concentrations are regulated by extracellular fluid volume; they are increased by dehydration, dietary sodium restriction, or sodium diuresis, and decreased by oral or intravenous sodium loading.
•Plasma potassium concentration – Aldosterone secretion is regulated in part by circulating potassium concentrations; circulating aldosterone levels increase with hyperkalemia and decrease with hypokalemia.
•Medication use – For initial testing for primary aldosteronism, aldosterone measurement does not require withholding potentially interfering medications [25,26]. Although withholding such medications was once recommended, this guidance has changed to facilitate testing given the underdiagnosis of primary aldosteronism. Nonetheless, concurrent medications should be considered when interpreting aldosterone levels. If initial testing results are equivocal or medication interference is suspected, potentially interfering agents typically should be withheld for two to four weeks prior to repeat aldosterone measurement when possible, and diuretics (eg, spironolactone) should be withheld for six weeks prior to testing. (See "Diagnosis of primary aldosteronism", section on 'Interfering drugs'.)
For aldosterone measurement for other indications, the approach to withholding medications prior to testing varies with the indication for measurement, the safety of withholding treatment, and the specific medication [27].
-Medications that increase aldosterone include diuretics (eg, spironolactone), beta blockers, clonidine, alpha-methyldopa, and nonsteroidal antiinflammatory agents (NSAIDs).
-Medications that decrease aldosterone include calcium channel blockers, angiotensin-converting enzyme inhibitors, direct renin inhibitors, and angiotensin receptor blockers.
If alternative hypertensive therapy is needed while interfering medications are withheld, verapamil slow-release and alpha blockers (eg, prazosin, moxonidine) minimally affect aldosterone measurements and may be used.
•Menstrual phase, exogenous progestogens, and pregnancy – Initial aldosterone measurement can be performed during any phase of the menstrual cycle. If initial results are equivocal, repeat sample collection ideally should be performed during menses or the follicular phase of the menstrual cycle. Aldosterone concentrations tend to increase in the luteal phase of the menstrual cycle, during which they are significantly higher in menstruating females than in age-matched males [9]. Exogenous progestogens also increase aldosterone levels, and aldosterone levels are increased up to 10 times normal by the third trimester of pregnancy [12,13].
●Sample collection – As for renin, blood samples for aldosterone measurement should be drawn in the morning while the patient is in an upright, seated posture.
•Time of day – Serum aldosterone concentrations show diurnal variation, with highest concentrations in the morning at approximately the time of awakening and lowest concentrations in the evening [28].
•Posture – With assumption of upright posture, plasma aldosterone rises [29]. This results partly from an increase in renin [18]. In addition, metabolic clearance of aldosterone decreases due to reduced hepatic blood flow [18].
RESULT INTERPRETATION
Values within the reference range — Renin and aldosterone levels within the reference range do not exclude an underlying, pathologic condition. They are usually within the reference interval in:
●Central adrenal insufficiency (panhypopituitarism or isolated corticotropin [ACTH] deficiency). (See "Causes of hypopituitarism".)
●Cushing syndrome. However, renin and aldosterone levels can be low if hypercortisolism is severe. (See 'Aldosterone low' below and "Epidemiology and clinical manifestations of Cushing syndrome".)
Renin — Expected morning plasma renin activity (PRA) values for seated, healthy individuals range from approximately 1 to 4 ng/mL per hour (0.8 to 3.0 nmol/L per hour). Corresponding direct renin concentration (DRC) values are 8 to 35 mU/L (13.3 to 58.4 ng/L or pg/mL). Reference ranges vary across clinical laboratories. (See 'Testing options' above.)
Aldosterone — Morning serum (and plasma) aldosterone concentrations, when measured by immunoassay, range from 5 to 30 ng/dL (140 to 830 pmol/L) in seated, healthy individuals with unrestricted sodium intake [30]. Levels tend to be approximately 25 percent lower when measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) [4]. (See 'Testing options' above and 'Key considerations for testing' above.)
Urinary aldosterone excretion ranges from approximately 5 to 19 mcg (14 to 53 nmol) per 24 hours in healthy individuals when measured by immunoassay. When measured by LC-MS/MS, levels also tend to be approximately 25 percent lower. Under pathologic conditions, urinary aldosterone excretion varies similarly to that described below for serum aldosterone.
Renin high — The approach to interpreting an elevated renin level depends on the corresponding aldosterone level.
Aldosterone high — Renin and aldosterone levels may be high in patients with secondary hyperaldosteronism due to elevated renin/angiotensin levels, as in the following:
●Renal artery stenosis or reninoma (causing renin-dependent hypertension). (See "Establishing the diagnosis of renovascular hypertension".)
●Malignant hypertension.
●Pseudohypoaldosteronism type 1, which results from pathogenic variants in the gene encoding the epithelial sodium channel (autosomal recessive) or mineralocorticoid receptor (autosomal dominant or sporadic). These variants lead to aldosterone resistance and salt wasting. (See "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1", section on 'Pseudohypoaldosteronism type 1'.)
●Heart failure, cirrhosis, and nephrotic syndrome, in which edema is associated with relative intravascular hypovolemia [31]. In heart failure and cirrhosis, aldosterone metabolism may be impaired.
●Use of diuretics (including spironolactone) or preparations containing progesterone or drospirenone, both of which antagonize aldosterone action at the mineralocorticoid receptor [7].
●Bartter syndrome or Gitelman syndrome, in which pathogenic variants in the genes encoding renal tubular ion channels lead to salt wasting. In these syndromes, aldosterone may be within the reference range if hypokalemia is present and partially inhibits aldosterone secretion. (See "Bartter and Gitelman syndromes in adults: Diagnosis and management".)
Aldosterone low (or undetectable) — Renin values are also elevated in conditions of mineralocorticoid deficiency, in which aldosterone levels are low or even undetectable. These include the following:
●Primary adrenal insufficiency. (See "Clinical manifestations of adrenal insufficiency in adults".)
In rare patients with longstanding central adrenal insufficiency, aldosterone deficiency can develop; however, renin and aldosterone levels are typically normal in central adrenal insufficiency. (See 'Values within the reference range' above and "Determining the etiology of adrenal insufficiency in adults", section on 'Establish the level of defect'.)
●Patients with congenital adrenal hyperplasia (CAH) due to deficiencies in steroidogenic acute regulatory protein (StAR), side-chain cleavage enzyme (CYP11A1), 3-beta-hydroxysteroid dehydrogenase (HSD3B2), 21-hydroxylase (CYP21A2) [32], or aldosterone synthase (CYP11B2) [33]. In these forms of CAH, deficient mineralocorticoid production leads to salt wasting. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Uncommon congenital adrenal hyperplasias".)
Renin low — Renin values are low in conditions that cause aberrantly increased mineralocorticoid signaling, as the resulting volume expansion suppresses renin release. Renin levels are also often low in patients with chronic kidney disease due to reduced renin-producing capacity and sodium retention [34].
Aldosterone high — Renin levels are low in association with elevated aldosterone levels in primary aldosteronism, in which aldosterone production is excessive relative to body sodium status and independent of its normal regulation by renin/angiotensin [31]. Primary aldosteronism may be due to an aldosterone-producing adrenocortical tumor, bilateral adrenal hyperplasia, or glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type I). (See "Pathophysiology and clinical features of primary aldosteronism" and "Familial hyperaldosteronism".)
In some patients with primary aldosteronism, aldosterone levels may be within the reference range but are inappropriately "normal" in the setting of excess body sodium and renin suppression [11,18].
Aldosterone low — Hyporeninemic hypoaldosteronism is associated with kidney disorders including diabetic kidney disease. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)
In salt-dependent, low-renin forms of hypertension, aldosterone concentrations are typically chronically low due to suppression of renin secretion. Low renin and aldosterone levels also are evident when aberrant activation of mineralocorticoid receptors occurs in the absence of hyperaldosteronism.
●Salt-dependent forms of hypertension include the following:
•Liddle syndrome, in which gain-of-function genetic variants in the epithelial sodium channel lead to sodium retention, hypertension, and usually hypokalemia [35]. (See "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1".)
•Familial hyperkalemic hypertension (also known as pseudohypoaldosteronism type 2 or Gordon syndrome), which causes sodium and potassium retention due to pathogenic variants in genes encoding serine-threonine kinases (WNK1 and WNK4) [36,37] or ubiquitinating enzymes (CUL3 and KLCH3) [38]. These variants lead to altered expression of the sodium-potassium cotransporter in the distal nephron. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Pseudohypoaldosteronism type 2 (Gordon's syndrome)'.)
Renin is usually low in familial hyperkalemic hypertension but may be within the reference range in some patients. If hyperkalemia limits aldosterone suppression, aldosterone levels also may not be overtly low.
●Aberrant mineralocorticoid receptor activation occurs in the following:
•Congenital or acquired (eg, through ingestion of licorice) deficiency of 11-beta-hydroxysteroid dehydrogenase type 2, which results in cortisol-mediated activation of the mineralocorticoid receptor [39,40]. (See "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)
•Pathogenic variants in the mineralocorticoid receptor gene, which cause a modest constitutive activation of the receptor and permit progesterone and spironolactone to act as agonists rather than antagonists [41]. (See "Genetic factors in the pathogenesis of hypertension", section on 'Monogenic (secondary) hypertension'.)
•CAH due to 11-beta-hydroxylase or 17-alpha-hydroxylase deficiency [42,43]. These hypertensive forms of CAH are associated with excessive production of the mineralocorticoid deoxycorticosterone (DOC). (See "Uncommon congenital adrenal hyperplasias".)
•Primary glucocorticoid resistance [44], which is associated with increased ACTH secretion and excessive DOC production, causing hypertension. (See "Uncommon congenital adrenal hyperplasias", section on 'Lipoid congenital adrenal hyperplasia'.)
•DOC-producing adrenal tumors [45]. (See "Diagnosis of primary aldosteronism".)
•Ectopic ACTH syndrome [46], in which cortisol levels may be high enough to overwhelm the 11-beta-hydroxysteroid dehydrogenase type 2 enzyme and lead to cortisol-mediated stimulation of the mineralocorticoid receptor [46]. In addition, high levels of ACTH may lead to excessive production of DOC. Other etiologies of Cushing syndrome may cause renin and aldosterone suppression if hypercortisolism is sufficiently severe. (See "Causes and pathophysiology of Cushing syndrome", section on 'Ectopic ACTH syndrome'.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary aldosteronism".)
SUMMARY
●Renin measurement – Renin can be measured in terms of its enzymatic activity (plasma renin activity [PRA]), or its mass (direct renin concentration [DRC]). PRA is more time-consuming but, if available, has some advantages over DRC. (See 'Testing options' above and 'Assay selection' above.)
•Prior to renin measurement, patients should have unrestricted dietary sodium intake (eg, 2500 to 4500 mg daily). Many medications affect renin levels. However, for initial testing for primary aldosteronism, renin measurement does not require withholding potentially interfering medications. (See 'Key considerations for testing' above and "Diagnosis of primary aldosteronism", section on 'Interfering drugs'.)
•Blood samples for renin measurement should be collected in the morning while the patient is upright and seated. Blood samples should be collected, transported, and processed at room temperature without chilling or icing.
●Aldosterone measurement – Aldosterone production may be assessed either by measuring serum (or plasma) aldosterone or urinary aldosterone secretion. Serum aldosterone is more commonly measured to avoid the inconvenience of 24-hour urine collection. (See 'Testing options' above.)
•Prior to aldosterone measurement, hypokalemia should be corrected with potassium chloride (KCl) supplements, and patients should follow a diet with unrestricted sodium intake (eg, 2500 to 4500 mg daily). For initial testing for primary aldosteronism, aldosterone measurement does not require withholding potentially interfering medications. (See 'Key considerations for testing' above and "Diagnosis of primary aldosteronism", section on 'Interfering drugs'.)
•As for renin, blood samples for aldosterone measurement should be drawn in the morning while the patient is in an upright, seated posture.
●Result interpretation
•Values within the reference range – Renin and aldosterone levels within the reference range do not exclude an underlying, pathologic condition. They are usually within the reference interval in central adrenal insufficiency and Cushing syndrome. (See 'Values within the reference range' above.)
•Renin elevated – Renin and aldosterone levels may be high in patients with secondary hyperaldosteronism due to elevated renin/angiotensin levels. (See 'Aldosterone high' above.)
Renin values are also elevated in conditions of mineralocorticoid deficiency, in which aldosterone levels are low or even undetectable. (See 'Aldosterone low (or undetectable)' above.)
•Renin low – Renin levels are low in association with elevated aldosterone levels in primary aldosteronism, in which aldosterone production is excessive relative to body sodium status and independent of its normal regulation by renin/angiotensin. (See 'Aldosterone high' above.)
In salt-dependent, low-renin forms of hypertension, aldosterone concentrations are typically chronically low due to suppression of renin secretion. Low renin and aldosterone levels also are evident when aberrant activation of mineralocorticoid receptors occurs in the absence of hyperaldosteronism. (See 'Aldosterone low' above.)
