Aldosterone and Renin-Angiotensin System

Sample

1. Aldosterone test can be done on plasma (heparin, EDTA, or citrate).
2. The serum can also be used.
3. Urine 24 hours is collected with boric acid, and during collection, it is refrigerated.
4. The patient should be resting and lying position for the first sample.
   1. The second sample can be taken when the patient is up and at least 4 hours of the first sample.
   2. The patient should be upright for at least 2 hours to collect the upright sample with unrestricted salt intake.
   3. Separate the serum/plasma immediately from the cells.
   4. Aldosterone peak is in the morning.
5. 24 hours of urine can also be used to measure aldosterone.
   1. A urine sample is preferred to avoid the variation of aldosterone levels.
   2. The urine sample needs to be acidified with strong mineral acids or boric acid.
   3. Keep the urine refrigerated or on the ice during the 24 hours immediately.
6. The patient should be without any medication for 3 weeks.
7.  The patient should be on a normal sodium diet for 2 to 4 weeks days before the test.
8. In case of low K⁺, should be treated before the test.
9. Label the sample whether the patient was lying or standing.
10. AM level is higher than the PM level.

Precautions

1. The patient should be on a normal salt diet for at least 2 weeks before the sample is taken.
2. Diuretics, anti-hypertensive drugs, estrogen, oral contraceptives should be terminated 2 to 4 hours before taking the sample.
3. No radioactive material should be given.
4. Transport the sample on ice and freeze as soon as possible after collecting the sample.
5. Stress and exercise can stimulate the increased production of aldosterone by the stimulation of the adrenal cortex.
6. Thermal stress, starvation, and late pregnancy may increase the level.
7. Values are affected by posture, diet, pregnancy, and diurnal variation.
   1. Values are increased by upright posture.
8. Increased intake of licorice can decreases the level of aldosterone. Stop it for at least 2 weeks before the sample is taken.
9. Drugs like diazoxide, hydralazine, diuretics, nitroprusside, potassium, and laxatives increase the aldosterone level.
10. Drugs like propranolol (Inderal) and captopril decrease the aldosterone level.
    1. Stop the propranolol one week before the sample is taken.
11. Heparin therapy may decrease the level.
12. Aldosterone level decreases with age.

Indications

1. Used to diagnose hyperaldosteronism.
2. It differentiates primary aldosteronism (Adrenal diseases) from secondary aldosteronism (Extra-adrenal diseases).
   1. A single random test for aldosterone is of no use unless plasma renin level is also done simultaneously.

Pathophysiology

1. Aldosterone is the adrenal gland hormone (produced in the zona glomerulosa of the adrenal cortex), and it helps to control electrolyte balance.
2. Aldosterone is the major mineralocorticoid  produced by the afrenal cortex 200 µg/day.
   

   Aldosterone secreted by the Adrenal glands from the zona glomerulosa

   

   Aldosterone secretion from the adrenal gland

Aldosterone functions:

1. The main function of aldosterone:
   1. It maintains the mineral regulation by its action on the distal convoluted tubule to increase sodium and chloride resorption.
   2. Aldosterone responds to the change in body volume. It accelerates the reabsorption of the Na⁺ in the distle tubules in exchange with K⁺ ions.
   3. When there is excess production of hormones, Na⁺ is retained, and K⁺ is excreted.
   4. If the hormone’s deficiency, then reverse action occurs,  increased Na⁺ excretion and retention of the K⁺ ions.
      

      Aldosterone effect on kidney
2. Aldosterone is secreted at the rate of 150 to 200 micrograms/day that regulates the salt contents and extracellular fluid level.
3. In case of profuse sweating, which led to the loss of NaCl and needed to conserve the Na⁺, that is because of aldosterone hormone.
4. Its action is on the renal distal convoluted tubule.
   1. It regulates sodium, Chloride, and water resorption in exchange for Potassium excretion and Hydrogen in the kidney.
      

      Aldosterone role on kidneys, regulate Na+ absorption and its excretion

5. Aldosterone helps and maintains blood pressure and blood volume.
   

   Aldosterone role for control of blood pressure and blood volume

The renin-angiotensin system controls the secretion of aldosterone.

1. 1. Renin is a proteolytic enzyme synthesized and stored in the juxtaglomerular cells located in the terminal part of afferent arterioles.
   2. The renin-angiotensin system regulates aldosterone secretion.
   3. The second controller is ACTH  which stimulates the production of Aldosterone. It depends upon:
      1. Low serum sodium level.
      2. High serum potassium level.
         

         Renin-angiotensin system leading to secretion of aldosterone

 

7. There is the production of angiotensin, which stimulates the secretion and synthesis of Aldosterone from the adrenal gland.
8. Potassium controls the secretion of aldosterone.
9. High level of potassium:
   1. increases the secretion of Aldosterone.
   2. While low level decreases production.
10. Low level of Sodium:
    1. It causes the release of Renin which again stimulates aldosterone secretion.

11. Aldosterone level has a diurnal variation:
    1. With a peak early in the morning.
    2. Lower level late in the afternoon.

Clinical significance:

1. 1. Usually, hyperaldosteronism is seen in the adenoma of the adrenal cortex (Conn’s syndrome) or bilateral adrenal nodular hyperplasia.
   2. An excessive level of aldosterone leads to the retention of sodium and potassium excretion.
      1. There are hypertension and hypokalemia.
      2. There are weaknesses and polyuria.
         

         Aldosterone function and S/S

Normal Level

Source 1

Adult	ng/dL
Supine position	3 to 16
Upright	7 to 30
Infants and children
Infant 3 days	7 to 184
1 to 12 months	5 to 90
1 to 2 years	7 to 54
2 to 10 years
Supine	2 to 22
Upright	4 to 48
Urine level 24 hours	<50 mcg/dL

Another source

• Adult
• Upright position sitting for 2 hours
  • Male = 6 to 22 ng/dL
  • Female = 5 to 30 ng/dL
• Newborn = 5 to 60 ng/dL

Source 2

• Adult
• Supine = 3 to 10 ng/dL
• Upright
  • Male = 6 to 22 ng/dL
  • Female = 5y to 30 ng/dL
• Newborn = 5 to 60 ng/dL
  • 1 week to 1 year = 1 to 60 ng/dL
  • 3 to 5 years = 5 to 80 ng/dL
  • 7 to 11 years = 5 to 70 ng/dL
  • 11 to 15 years =5 to 50 ng/dL
• Urine = 2 to 26 µg /24 hours

Source 4

• Normal in upright position
  • Adult = 7 to 30 ng/dL (0.19 to 0.83 nmol/L)
  • Adolescent = 4 to 48 ng/dL (0.11 to 1.33 nmol/L)
  • Children = 5 to 80 ng/dL (0.14 to 2.22 nmol/L)
  • Low- sodium diet = 3 to 5 times higher values

Primary hyperaldosteronism:

1. These patients signs and symptoms:
   1. Primary hyperaldosteronism also called Comm’s syndrome, result from an overproduction of aldosterone, usually by an adrenal cortex adenoma, and other causes are carcinoma and nodular hyperplasia.
   2. Hypertension.
   3. Muscular pains and cramps.
   4. Weakness.
   5. Tetany.
   6. Paralysis.
   7. Polyuria.
   8. Low Potassium level.
2. Causes of primary hyperadrenalism:
   1.  70% of cases are due to aldosterone-producing tumor-like adrenal cortical adenoma in 54 to 90%.
      1. CT scan can diagnose 75% of the cases ( range is 60% to90%).
      2. In few centers, they do adrenal vein catheterization and get samples from both side veins. If there is a significant difference between both sides, suggest adenoma.
   2.  30% of cases are caused by idiopathic bilateral adrenal hyperplasia; the range is 10% to 45%.
   3. Adrenal carcinoma is seen in <5% of the cases.
   4. Ectopic production of the aldosterone by the adrenal gland embryologic rest within kidneys, or rarely ovaries.
   5. Ectopic production of the ACTH or aldosterone by nonadrenal tumors.
3. Lab findings are:
   1. Decreased serum K⁺.
   2. Increased aldosterone production can not be suppressed by an increase in the volume or increased Na⁺ intake.
      1. There is a diurnal variation of aldosterone, lower values in the afternoon than in the morning.
      2. Also, there is an increased level in the upright position.
   3. There is suppressed plasma renin activity. this is a characteristic lab finding.
   4. Urinary secretion of aldosterone is increased. Urine estimation has the advantage of eliminating the fluctuation.

4. Lab diagnosis of primary hyperaldosteronism:

5. Primary hyperaldosteronism depends on three criteria:
   1. Hypertension without edema.
   2. Low plasma renin level that fails to increase with volume depletion.
   3. Increased aldosterone that fails to decrease with saline or angiotensin inhibition.
6. Aldosterone stimulation test.
   1. Restrict the salt, and the Renin level will show little or no rise.
7. Aldosterone suppression test.
   1. Give normal saline 1.5 to 2 L between 8 AM to 10 AM. Aldosterone will not be suppressed.
   2. A single random test of aldosterone is of no diagnostic value unless plasma renin activity is done simultaneously.

Secondary hyperaldosteronism:

1. Usually associated with extra-adrenal stimulation or non-adrenal causes. e.g.
   1. Renal vascular stenosis or occlusion.
   2. Hypovolemia.
   3. Hyponatremia from diuretic or laxatives or low salt intake.
   4. Malignant hypertension.
   5. In case of pregnancy or use of estrogens.
   6. Edematous diseases like congestive heart failure, nephrotic syndrome, or cirrhosis.
   7. Potassium loading.

Aldosterone Raised Level is seen in:

1. In adrenocortical adenoma or carcinoma.
2. Bilateral hyperplasia of the adrenal gland.
3. Liver diseases.
4. Congestive heart failure (CHF).
5. Cirrhosis.
6. Pregnancy.
7. Nephrotic syndrome.
8. Renovascular hypertension.

Different values of aldosterone and renin in various diseases:

Causes of the aldosteronism	Aldosterone level	Renin level
Primary hyperaldosteronism	Increased	Decreased
Cushing’s syndrome	Decreased to normal	Decreased
Ingestion of the licorice	Decreased	Decreased
High salt diet	Decreased	Decreased
Cirrhosis	Increased	Increased
Malignant hypertension	Increased	Increased
Pregnancy	Increased	Increased
Low salt diet	Increased	Increased
Addison disease	Decreased	Increased
Hypokalemia	Decreased	Increased

Aldosterone Decreased level is seen in:

1. In primary hyperaldosteronism.
2. Salt losing diseases.
3. Toxemia of pregnancy.

Decreased Aldosterone without hypertension seen in:

1. Addison’s Disease.
2. Syndrome of hyperaldosteronism due to renin deficiency.
3. Isolated cases of aldosterone deficiency.

Decreased Aldosterone with hypertension seen in:

1. Excessive secretion of corticosterone.
2. Excessive secretion of Deoxycorticosterone.
3. Excessive secretion of 18-hydroxydesoxycorticosterone.
4. Turner’s syndrome (in some cases).
5. Diabetes mellitus.
6. Acute alcoholic intoxication.

Clinical conditions of Aldosterone:

Clinical condition	Aldosterone	Potassium	Blood pressure	Renin activity
Primary hyperadrenalism	Increased	Low	High	decreased
Primary hypoadrenalism	Decreased	High	Low	Increased
Secondary hyperadrenalism	Increased	Low or low normal	Usually high	Increased

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