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Do you have high blood pressure and are not sure why? Is your blood pressure still high, despite lifestyle changes or medication? Renin may hold the answer. Produced by the kidneys, this enzyme helps control blood pressure and fluid balance. Without renin, our bodies would not be able to maintain blood pressure when we lose salt. Because both high and low levels of renin underlie high blood pressure, measuring your renin levels can help you uncover the causes of hypertension and determine the right course of treatment. Read on to find out what a renin blood test can reveal about your health.
What is Renin?
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. 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) [R, R, R].
Renin is mainly produced by special cells in the kidney (juxtaglomerular cells) in response to [R]:
- 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)
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. 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 [R, R].
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 [R].
The renin-angiotensin system is also involved in red blood cell production and thickening of the heart muscle (hypertrophy) [R].
While high renin can increase blood pressure via the RAS, low renin can also increase blood pressure [R].
Renin Blood Test
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) [R].
Another method is measuring plasma renin concentration (PRC, pg/ml). Compared to PRA, the PRC is faster, easier to perform, and reproducible. However, unlike the PRA, it is not sensitive in measuring low levels of renin [R+, R+].
- 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
Normal Renin Levels
Normal plasma renin activity levels range from 0.25 – 5.82 ng/mL/hr.
Normal ranges may vary among different labs.
Causes of Low Renin Levels
3) High Dietary Sodium
4) Too Much Fluid in the Blood
Because high blood volume inhibits renin production, fluid overload (hypervolemia) leads to low blood renin levels [R].
Renin levels are reduced in approximately a quarter of patients with essential hypertension. This is due to higher blood pressure at the cells that produce renin (juxtaglomerular cells), which suppresses renin release [R].
6) Kidney Dysfunction
Conditions that lead to kidney cell (nephron) loss and dysfunction can lead to low renin and aldosterone levels. These include [R]:
- 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)
Blood renin activity levels were lower in 15 people with hypothyroidism compared to healthy people. This may be a result of decreased renin production, in part owing to decreased sympathetic activity in the kidney (i.e. b-adrenergic activity) [R+, R+].
Thyroid hormone treatment increased plasma renin activity levels in a study of 22 people with primary myxoedema (severe hypothyroidism) [R].
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 [R].
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 [R, R].
The most common causes of primary hyperaldosteronism are [R+]:
- 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 [R].
9) Salt-Sensitive Hypertension
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. Salt-sensitive hypertension is usually associated with impaired kidney function, which results in the failure of the kidneys to properly excrete sodium and water [R+, R].
- 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
- 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 effective in lowering blood pressure [R].
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 [R, R].
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) [R].
11) High Licorice Intake
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 [R+].
- 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)
Symptoms of Low Renin
- High blood pressure
- Muscle weakness
Consequences of Low Renin
- 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 [R].
How to Increase Renin
1) Address Underlying Health Conditions
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
2) Eat a Lower Sodium Diet
Normally, eating too much salt suppresses the release of renin. Thus, in healthy, non-salt-sensitive people, reducing salt can raise renin levels [R].
Cutting back on salt is also beneficial for salt-sensitive people, whose blood pressure rises in response to salt intake [R].
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 [R+].
3) Lower Blood Pressure
The following have been shown to lower blood pressure in humans.
- Aerobic exercise [R+]
- Healthy diet: eating a diet rich in fruits and vegetables and limiting the intake of snacks and sweets can lower blood pressure [R].
- Increasing potassium [R+]
- Lose Weight – 0besity can increase the risk of high blood pressure [R+, R+].
- Cut nicotine, which raises blood pressure and increases heart rate [R, R+].
Causes of High Renin
1) Menstrual Cycle Phase
Renin activity levels increase during the luteal phase of a menstrual cycle in women [R+].
In a study of 10 people, plasma renin activity increased with decreased blood volume due to dehydration [R+].
3) Upright Body Posture
An upright body posture slightly decreases blood pressure, which stimulates renin production. One study in 10 people found that assuming an upright posture increased plasma renin activity [R+].
The renin-angiotensin system (RAS) is more active during pregnancy. In early pregnancy, the kidneys produce more renin and the ovaries and uterine lining produce an inactive renin precursor (prorenin). Also, as the placenta grows, it produces estrogen, which increases angiotensinogen production by the liver, leading to increased blood angiotensin II [R, R, R].
Because of an increase in aldosterone, pregnant women have higher blood volume [R].
Stress increases sympathetic activity, which stimulates renin production. In a study of 20 people (10 with high blood pressure, 10 healthy), mental stress increased plasma renin activity in both groups [R, R].
6) Strenuous Exercise
In a study of 33 runners, plasma renin activity increased 3-fold after a marathon run [R].
Plasma renin activity levels were elevated in 24 people with hyperthyroidism (likely due to increased sympathetic activity) [R].
8) Addison’s disease
Adrenal glands that do not make enough aldosterone and other hormones (e.g Addison’s disease or other adrenal gland insufficiencies) can cause elevated renin activity levels. This is because a lack of aldosterone leads to increased sodium excretion, which lowers blood sodium levels and subsequently, blood volume and pressure. This drop in blood sodium levels activates renin production in the kidney [R].
9) Low Blood Volume
Low blood volume activates renin production. Conditions that lead to low blood volume include:
- Bleeding (hemorrhage)[R, R]
- Heart failure [R]
- Nephrotic syndrome (kidney disorder that causes excess protein in the urine) [R]
10) Renal Artery Stenosis
Hardening of the arteries (atherosclerosis) is the most common cause of renal artery stenosis [R].
11) Malignant Hypertension
Malignant hypertension is defined as sudden and very high blood pressure that causes organ damage. In a study of 30 people with malignant hypertension (n=18) and severe hypertension (n=12), plasma renin activity and aldosterone levels were significantly elevated in those with malignant hypertension but not in severely hypertensive people despite minimal differences in blood pressure [R].
This may occur due to the damage of small kidney blood vessels caused by severe hypertension, which results in reduced blood flow in the kidneys. This activates renin production, which in turn may result in further blood vessel damage [R].
Reninomas are rare tumors of the kidney cells that make renin (juxtaglomerular cell tumors). They produce excessive amounts of renin, resulting in severe hypertension, high aldosterone levels, and low blood potassium levels [R, R].
13) Liver Scarring
Liver scarring (cirrhosis) promotes fluid buildup within the abdomen (ascites). This leads to decreased circulating blood volume, which stimulates renin production [R].
Pheochromocytoma is a rare, usually benign tumor that develops in the adrenal gland. It causes the adrenal gland to make too many hormones (catecholamines). In a study of 7 people with pheochromocytoma, plasma renin activity remained high after suppression with saline in 4 people and decreased into the normal range in all 4 people after surgical removal of pheochromocytoma [R+].
- Dihydropyridine calcium channel blockers
- Angiotensin-converting enzyme (ACE) inhibitors
- Angiotensin receptor antagonists
Consequences of High Renin
1) Higher Death Risk
Higher plasma renin levels were associated with the risk of dying from all causes in an observational study of 3200 people (1413 with high blood pressure) [R].
2) Heart Disease
Higher plasma renin activity levels were associated with a greater risk of heart attack (regardless of blood pressure) in a study of 1717 people with mild to moderate hypertension [R].
Plasma renin concentration was associated with long-term mortality due to heart disease in 3303 patients referred to coronary angiography (x-ray imaging to examine the blood vessels of the heart) [R].
4) Chronic Kidney Disease (CKD)
Higher levels of PRA are associated with greater rates of CKD in 9500 people (the majority with high blood pressure) [R+].
How to Decrease Renin
1) Address Underlying Health Conditions
The following conditions must be resolved in order to normalize renin levels.
- Thyroidectomy (surgical removal of the thyroid)
- “Antithyroid” medications such as Tapazole (methimazole) and propylthiouracil (which stop thyroid hormone synthesis) or cholestyramine (which promotes excretion of excess thyroid hormones)
- Beta-blockers like propranolol, atenolol, and nadolol can be taken to ease hyperthyroid symptoms
b) Addison’s Disease
c) Renal Artery Stenosis
Treatment mainly consists of controlling high blood pressure with drugs/lifestyle changes [R+].
If hardening of the arteries (atherosclerosis) is the underlying cause, drugs that lower cholesterol may be prescribed [R].
For more severe cases, surgery is used to restore blood flow to the kidneys [R].
Drugs that lower blood pressure may be prescribed to reduce symptoms [R].
Surgically removing the tumor restores normal blood pressure in a majority of patients with reninoma [R].
e) Liver Scarring (Cirrhosis)
If you have liver scarring (cirrhosis), liver health can be improved by:
- Eating a well-balanced diet [R]
- Drinking moderate to high (>3 cups) amounts of coffee (regardless of caffeine content) on a regular basis [R, R+]
- Getting more quality sleep [R+]
- Eating more foods that can help detoxify the liver and kidneys such as asparagus, cabbage, and broccoli [R]
- Drinking more water [R]
- Buying organic meats and vegetables whenever possible to avoid chemical additives and pesticides that damage the liver [R]
- Going to the sauna – saunas are beneficial for decreasing toxins in the body [R]
- Limiting your alcohol intake – excess alcohol can damage liver cells and worsen existing liver conditions [R]
- Reviewing your medications – some drugs or supplements can damage the liver. Have a doctor or pharmacist review your medications to see if any could be harmful to the liver [R, R]
2) Stay Hydrated
Drinking enough water and making sure you are well hydrated, which helps increase blood volume, and in turn decrease renin [R+].
3) Manage Stress Levels
Note: By writing this section, we are not recommending these drugs. We are simply providing information that is available in the scientific literature. Please discuss your medications with your doctor.
- Certain drugs that treat high blood pressure (e.g. beta-blockers, clonidine, alpha-methyldopa)
- Nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors
- Heparin (a drug that treats blood clots)
Genetics of Renin
The following genetic conditions are associated with abnormal renin levels.
Gene Mutations and Low Renin
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) [R].
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 [R, R].
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 [R].
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 [R].
In the kidneys, the proteins WNK1 and WNK4 activate the electrolyte transporters Na+/Cl– 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 [R+, R+, R+, R+].
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 [R].
- 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 [R].
5) Congenital Adrenal Hyperplasia (CAH)
CAH is a genetic adrenal gland disorder caused by mutations in genes encoding enzymes involved in cortisol production [R].
6) Glucocorticoid Resistance
Familial glucocorticoid resistance is a rare syndrome characterized by reduced cortisol activity [R].
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 [R].
People with glucocorticoid resistance typically experience [R]:
- Low renin hypertension
- Low potassium levels
- Excessive body hair, or hirsutism (for women)
- Hair loss (for men)
- Early puberty
- Period irregularities
- Chronic fatigue
Gene Mutations and High Renin
1) Bartter’s Syndrome
Bartter’s syndrome is a rare inherited defect of the kidney cells in the part of the kidney that reabsorbs electrolytes (loop of Henle) and is characterized by [R+]:
- High blood renin levels
- Potassium wasting
- Low blood chloride levels
- Metabolic alkalosis (high blood pH)
- High aldosterone secretion
- Normal blood pressure
- High urine prostaglandin levels
- Frequent need to drink and urinate
The syndrome is caused by mutations in the Na+/K+/2Cl– cotransporter 2 (NKCC2), as well as in the following related proteins [R+]:
- ROMK (a protein that moves potassium out of the cells)
- ClC-Kb (a protein that moves chloride out of the cells)
- CaSR (a protein that detects calcium levels and uses them as a signal to activate electrolyte transporters)
2) Gitelman’s Syndrome
Gitelman’s syndrome is a hereditary disease with similar symptoms to Bartter’s (metabolic alkalosis with low potassium, low chloride, high renin, and high aldosterone levels in the blood), but due to defects in the kidney cells of a different region (distal convoluted tubule). The condition is caused by mutations in the Na+/Cl– cotransporter (NCCT) [R+, R+, R].
When people go to their doctor to get their renin tested, the results are not scrutinized, even though we know that you can be healthier and live longer when your results lie within optimal ranges. When I used to go to doctors and tried to discuss my results, they had no clue what these meant from a health perspective. All they cared about was whether they could diagnose me with some disease. This is why we created Lab Test Analyzer, a tool that easily lets you know which lab results you need to be concerned about, and how to bring these within the optimal range.
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