High blood pressure is a common health concern, and it may point to abnormal renin. Produced by the kidneys, this enzyme helps control blood pressure and fluid balance. Without renin, we would not be able to maintain blood pressure when we lose salt. Both high and low levels of renin may underlie high blood pressure, but this post focuses on the renin blood test in general, normal, and low levels.
What is Renin?
Overview
Our bodies maintain a delicate balance with blood pressure in order to deliver appropriate amounts of oxygen and nutrients to every cell in the body. Because we are regularly flooding our blood with chemicals that shift this balance, the control is dynamic [1, 2].
One way the body exerts this control is through renin, an enzyme responsible for initiating a cascade of events in response to low blood pressure. These events are collectively known as the renin-angiotensin system (RAS) [1, 2].
Renin Production
Renin is mainly produced by special cells in the kidney (juxtaglomerular cells) in response to [3]:
- Low arterial blood pressure (that can be related to a decrease in blood volume)
- Decreased blood sodium levels
- Increased sympathetic nervous system activity (i.e. β1 adrenergic receptors)
Conversely, renin production is inhibited by high blood pressure, excess salt, and fluid overload [4].
Renin-Angiotensin System (RAS)
When renin is released by the kidneys into the bloodstream, it converts angiotensinogen, a protein produced by the liver, into angiotensin I [5, 3].
Next, an enzyme produced in the lungs called angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II.
Angiotensin II causes blood vessels to constrict and stimulates the production of aldosterone, a hormone that signals kidneys to retain salt and water. Overall, this helps raise blood pressure and blood volume and maintain normal sodium and potassium levels [5, 3].
However, if this process gets out of balance, blood pressure can get too high. Since renin and aldosterone are closely related, they are often tested together in people with high blood pressure to identify the cause of abnormal aldosterone levels [3].
The renin-angiotensin system is also involved in red blood cell production and abnormal thickening of the heart muscle (hypertrophy) [6].
While high renin can increase blood pressure via the RAS, low renin can also increase blood pressure [7].
Renin Blood Test
Active Renin (PRA)
Renin is most commonly measured as plasma renin activity (PRA), or “active renin”. Plasma renin activity is a measure of the capacity of renin to generate angiotensin I (precursor of angiotensin II) [1].
Renin Concentration (PRC)
Another method is measuring plasma renin concentration (PRC, pg/ml). Compared to PRA, PRC is faster, easier to perform, and reproducible. However, unlike PRA, it is not sensitive in measuring low levels of renin [8+, 9+].
Normal Renin Levels
Lab results are commonly shown as a set of values known as a “reference range”, which is sometimes referred to as a “normal range”. A reference range includes the upper and lower limits of a lab test based on a group of otherwise healthy people.
Your healthcare provider will compare your lab test results with reference values to see if any of your results fall outside the range of expected values. By doing so, you and your healthcare provider can gain clues to help identify possible conditions or diseases.
Normal plasma renin activity (PRA) levels range from 0.25 – 5.82 ng/mL/hr.
Normal ranges may vary among different labs.
Because renin release is controlled by multiple variables, a number of factors can affect the interpretation of your results, including [10, 11+, 12+]:
- Your posture
- The medications you take
- Menstrual cycle – renin activity levels increase during the luteal phase of a menstrual cycle in women
- Your sodium intake
- The time of day – renin levels peak in the early morning and decline in the late afternoon
Some lab-to-lab variability occurs due to differences in equipment, techniques, and chemicals used. Don’t panic if your result is slightly out of range — as long as it’s in the normal range based on the laboratory that did the testing, your value is normal.
However, it’s important to remember that a normal test doesn’t mean a particular medical condition is absent. Your doctor will interpret your results in conjunction with your medical history and other test results.
Have in mind that a single test isn’t enough to make a diagnosis. Your doctor will interpret this test, taking into account your medical history and other tests. A result that is slightly low/high may not be of medical significance, as this test often varies from day to day and from person to person.
Low Renin
Causes
Causes shown here are commonly associated with low renin. Work with your doctor or other health care professional for an accurate diagnosis.
1) Age
Blood renin levels fall by 17% each decade. This may be a result of age-related structural changes in the kidneys and decreased renin production [1, 7, 13, 14].
2) Ethnicity
Low plasma renin activity is common in younger people of African descent, which is attributed to reduced renin production. However, the exact mechanisms are unclear [7, 15+].
3) High Dietary Sodium
Excessive sodium intake normally inhibits renin production [16, 17, 18, 19+].
4) Too Much Fluid in the Blood
Because high blood volume inhibits renin production, fluid overload (hypervolemia) leads to low blood renin levels [7].
5) Hypertension
Renin levels are reduced in approximately a quarter of patients with essential hypertension. This is thought to be due to higher blood pressure at the cells that produce renin (juxtaglomerular cells), which suppresses renin release [7].
6) Kidney Dysfunction
Conditions that lead to kidney cell (nephron) loss and dysfunction can lead to low renin and aldosterone levels. These include [7]:
- Diabetic nephropathy (diabetic kidney disease)
- Chronic glomerulonephritis, a type of kidney inflammation
- Congenital solitary kidney (one kidney does not function)
- Unilateral nephrectomy (surgical removal of one kidney)
- Aging
7) Hypothyroidism
Blood renin activity levels were lower in 15 people with hypothyroidism compared to healthy people. Scientists believe this may be a result of decreased renin production, in part owing to decreased sympathetic activity in the kidney (i.e. b-adrenergic activity) [20+, 21+].
Additionally, some scientists think this might explain why hypothyroid patients typically have excess fluid buildup in tissues, resulting in edema (swelling) [21+].
Low renin activity in hypothyroidism may also shed light on why some hypothyroid patients experience hypertension [21+, 7].
Thyroid hormone treatment increased plasma renin activity levels in a study of 22 people with primary myxoedema (severe hypothyroidism) [22].
8) Primary Hyperaldosteronism
Primary hyperaldosteronism is when the adrenal glands release too much aldosterone (hyperaldosteronism), resulting in increased potassium loss and sodium retention. In turn, the excess sodium holds on to water, thereby increasing blood volume and pressure [7].
Over time, the increase in blood volume and pressure suppresses renin production. For this reason, people with primary hyperaldosteronism generally have very low renin levels as well as high aldosterone levels. They often also have low potassium levels [7, 23].
The most common causes of primary hyperaldosteronism are [24+]:
- Adrenal adenoma or Conn’s syndrome (benign tumor of the adrenal glands)
- Bilateral adrenocortical hyperplasia (both adrenal glands are hyperactive and make too much aldosterone)
Low renin levels differentiate primary (i.e. due to a problem of the adrenal glands themselves) from secondary (i.e. indirect) causes of hyperaldosteronism [7].
9) Salt-Sensitive Hypertension
Salt-sensitive high blood pressure is a condition in which blood pressure rises when excess salt is consumed and falls when salt intake is reduced [25, 26].
Normally, a high-salt diet suppresses renin production. However, in 40-50% of people with primary hypertension, increasing salt intake does not sufficiently reduce renin production. This leads to higher blood pressure when salt is consumed [27+, 5].
Salt-sensitive hypertension is usually associated with impaired kidney function, which results in the failure of the kidneys to properly excrete sodium and water [27+, 5].
Research suggests that many other factors may influence how blood pressure responds to salt, including [14, 5, 26]:
- Sex: women are more likely to be salt sensitive than men
- Genes: variants in the GRK4 gene are highly associated with salt sensitivity in humans
- Age: the likelihood of salt sensitivity increases with age
- Obesity
- Race and ethnicity: salt sensitivity is common in African Americans
- Clinical conditions: hypertension, diabetes, and chronic kidney disease all increase the risk of developing salt sensitivity
For these people, reducing salt intake is considered to be effective in lowering blood pressure [28].
10) Cushing’s Syndrome
Cushing’s syndrome is a hormonal disorder caused by chronically high blood levels of cortisol. Excess cortisol levels can activate certain receptors in the kidney (mineralocorticoid receptors), which leads to potassium excretion and sodium and water retention. In turn, water retention increases blood volume and pressure and ultimately decreases renin levels [7, 10].
One study (n=19) found that plasma renin activity levels were suppressed in more than half of people with Cushing syndrome due to adrenal hyperplasia (overactive adrenal glands) [29].
11) High Licorice Intake (from glycyrrhizin)
Excess licorice consumption can increase sodium and water retention and potassium excretion, resulting in high blood pressure and decreased blood renin levels [7, 30].
In a case study of a man who consumed excess licorice daily for 4-5 years with high blood pressure, increased sodium and water retention, and low potassium levels, discontinuing licorice intake cured his condition [31+].
Have in mind that these negative effects on the heart are due to a compound in licorice called glycyrrhizin. Deglycyrrhizinated licorice supplements (DGL) shouldn’t carry this risk as glycyrrhizin has been removed from them [32].
12) Certain Drugs
Drugs that may decrease renin activity levels include [7, 33+]:
- Drugs that treat high blood pressure (e.g. beta-blockers, clonidine, alpha-methyldopa)
- Aspirin/Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Heparin (a drug that treats blood clots)
- Vasopressin
Please discuss your medications with your doctor.
Symptoms
Symptoms depend on the underlying cause of low renin activity.
Possible signs and symptoms of excess aldosterone include [7, 34]:
- High blood pressure
- Headaches
- Muscle weakness
Associations
Anemia
A meta-analysis of seven studies with 29k patients found a significant association between anemia and the use of drugs that block the renin-angiotensin system. These drugs are usually prescribed to manage high blood pressure. In the study [35, 6]:
- People who took ACE inhibitors had a 1.56-fold increased risk of anemia
- People who took angiotensin II receptor blockers (ARB) had a 1.60-fold increased of risk anemia
Also, people with mutations in the gene encoding renin (REN) that result in low renin levels typically suffer from anemia in childhood. The reason for this is unknown, however, the role of renin and the RAS in red blood cell production is thought to play a role [36].
More research on this association is needed.
Management of Low Renin Levels
Addressing Underlying Health Conditions
If you have low renin levels, your doctor will recommend treatment and monitoring based on the underlying cause.
For example, the following conditions must be resolved in order to normalize renin levels:
- Low thyroid hormones (Hypothyroidism)
- High aldosterone (Hyperaldosteronism) – read more about aldosterone.
- Cushing’s Syndrome
This list is not exhaustive.
Once the underlying cause of low levels is under control, you may talk to your healthcare provider about lifestyle changes and complementary approaches that may help.
Below are some approaches to bring up with your doctor. These are typically recommended to people with low renin and high blood pressure.
Complementary Approaches
You may try the diet- and lifestyle-based interventions discussed below if you and your doctor determine that they could be appropriate.
Remember that these complementary approaches should ever be done in place of what your doctor recommends or prescribes.
For People with High Blood Pressure
The following have been shown to lower blood pressure in humans.
- Aerobic exercise [37+]
- Healthy diet: eating a diet rich in fruits and vegetables and limiting the intake of snacks and sweets [38].
- Increase dietary potassium [39+]
- Lose weight – obesity can increase the risk of high blood pressure [40+, 41+].
- Quit smoking. Cigarette toxins and nicotine raise blood pressure and increases heart rate [42, 43+].
Diet
Normally, eating too much salt suppresses the release of renin. Thus, in healthy, non-salt-sensitive people, reducing salt can raise renin levels [10].
Cutting back on salt is also beneficial for salt-sensitive people, whose blood pressure rises in response to salt intake [28].
However, limiting sodium too much can be harmful. In a meta-analysis of 58 studies, drastic sodium restriction led to an increase in LDL (“bad”) cholesterol without a boost in HDL cholesterol, although the same people had a 3.6 times increase in renin levels [44+].
Since sodium is lost through sweat, people engaged in extreme physical exercise or exposed to heat should avoid over-restricting their sodium intake [45+, 46].
Gene Mutations and Low Renin
Research Limitations
The following genetic conditions are associated with low renin levels.
It’s important to note that just because certain genotypes are associated with a disease, it doesn’t necessarily mean that everyone with that genotype will actually develop the disease!
Many different factors, including other genetic and environmental factors, can influence the risk of abnormal renin levels.
Associated Conditions
1) Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)
Mutations in the gene that codes for renin (REN) that result in low renin levels are a cause of a rare inherited kidney disease that affects the tubules of the kidneys known as autosomal dominant tubulointerstitial kidney disease (ADTKD) [36].
Many people with this disease typically suffer from anemia in childhood. Often, their blood potassium and uric acid levels are mildly elevated [36].
As the condition progresses, the kidneys lose their ability to filter waste products from the body, resulting in kidney failure. Affected people eventually require dialysis (to remove wastes from the blood) or a kidney transplant in the later stages of the disease [47, 36].
2) Gordon’s Syndrome
Pseudohypoaldosteronism type II (PHAII), also known as Gordon’s syndrome, is a rare hereditary disease characterized by low blood renin levels [7].
In this disorder, the kidneys absorb more sodium and excrete less potassium, leading to high blood sodium levels and potassium levels. This suppresses renin production [7].
In the kidneys, the proteins WNK1 and WNK4 activate the electrolyte transporters Na+/C- cotransporter (NCC) and Na+/K+/2Cl- cotransporters 1 and 2 (NKCC1 and NKCC2), thus causing the increased intake of sodium, chloride, and potassium. Additionally, the proteins KLHL3 and CUL3 form a complex that binds to WNK4 and breaks it down, thus decreasing the absorption of these electrolytes. Mutations in all these proteins can cause Gordon’s syndrome [48+, 49+, 50+, 51+].
3) Liddle’s Syndrome
Liddle’s syndrome is a rare genetic disorder in which the collecting tubules of the kidneys retain too much sodium and water, thereby causing low renin levels and high blood pressure [10].
This syndrome is caused by mutations in either the SCNN1A, SCNN1B, or SCNN1G genes [10].
People with Liddle’s syndrome generally have [10, 52]:
- Early onset hypertension
- Low plasma renin activity
- Low aldosterone levels and low potassium levels
4) Apparent Mineralocorticoid Excess Syndrome (AME)
The AME syndrome is a genetic disorder that is caused by the deficiency of an enzyme (11-beta-HSD2), resulting in excess cortisol levels. In turn, excess cortisol binds to receptors in the kidney (mineralocorticoid receptors), which leads to potassium excretion and sodium and water retention. Overall, this leads to decreased renin levels [7].
5) Congenital Adrenal Hyperplasia (CAH)
CAH is a genetic adrenal gland disorder caused by mutations in genes encoding enzymes involved in cortisol production [10].
Mutations in the CYP17A1 and CYP11B1 genes that cause deficiencies in the enzymes 7- Alpha-Hydroxylase and 11-Beta-Hydroxylase lead to low renin levels [10, 53].
6) Glucocorticoid Resistance
Familial glucocorticoid resistance is a rare syndrome characterized by reduced cortisol activity [54].
It is caused by mutations of the glucocorticoid receptor gene (NR3C1) which leads to high cortisol levels and increased ACTH. The excess cortisol binds to certain receptors in the kidney (mineralocorticoid receptors), which leads to low renin levels [10].
People with glucocorticoid resistance typically experience [10]:
- Low renin hypertension
- Low potassium levels
- Excessive body hair, or hirsutism (for women)
- Hair loss (for men)
- Acne
- Early puberty
- Period irregularities
- Chronic fatigue
