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Physiology II
Renal
Renal Regulation of Na+ and Effective Circulating Volume

(Ch. 6, Koeppen and Stanton)

Be familiar with the role and mechanism of action of the renin-angiotensin-aldosterone system.

Activation of the renin-angiotensin-aldosterone system results in a decrease in the excretion of sodium and water by the kidneys. Three factors which play an important role in stimulating renin secretion are the following:

  1. Perfusion Pressure- The afferent arteriole acts as a high-pressure baroreceptor. When perfusion pressure to the kidneys is reduced, renin secretion is stimulated. Conversely, renin release is inhibited with an increase in perfusion pressure.
  2. Sympathetic Nerve Activity- Activation of the sympathetic nerve fibers innervating the afferent and efferent arterioles results in increased renin secretion. And as renal sympathetic nerve activity decreases, renin secretion decreases.
  3. Delivery of NaCl to the macula densa- This regulates the GFR by a process termed tubuloglomerular feedback. By this feedback mechanism, increased NaCl delivery to the macula densa (in the juxtaglomerular apparatus) results in decreased GFR. Conversely, an increase in NaCl delivery inhibits renin secretion.

Renin does not have a physiologic function by itself. Its substrate is a circulating protein, angiotensinogen, which is produced by the liver. Angiotensinogen is cleaved by renin to yield a 10-amino-acid peptide, Angiotensin I (which has no known physiologic function) and is further cleaved to an 8-amino-acid peptide, Angiotensin II by Angiotensin-Converting-Enzyme [ACE]. Pulmonary and renal endothelial cells are important sites for the conversion of Angiotensin I to Angiotensin II. Several important functions of Angiotensin II include the following:

  1. Stimulation of aldosterone secretion by the adrenal cortex.
  2. Arteriolar vasoconstriction, which increases blood pressure.
  3. Stimulation of ADH secretion and thirst.
  4. Enhancement of NaCl resorption by the proximal tubule

Aldosterone acts in a number of ways on the kidneys. With regard to the regulation of ECV, aldosterone reduces NaCl excretion by stimulating its reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct. Activation of the RAA, as occurs with a decrease in the ECV, results in decreased excretion of NaCl by the kidneys. This system is suppressed when the ECV is expanded, and renal NaCl excretion is then enhanced.

See Figure 6-2, pg. 8 of Dr. Johnson’s handout (Regulation of Sodium and Effective Circulating Volume) Schematic representation of the essential components of the renin-angiotensin-aldosterone system.

Have a good understanding of the normal handling of the filtered Na+ filtered load by the proximal tubule, loop of Henle, distal tubule, and collecting tubules.

In a normal adult, the filtered load of Na+ can be calculated:

Filtered load of Na+  

= (GFR) (plasma [Na+])
= (180L/day) (140mEq/L)
= 25,200 mEq/day

 With a typical diet, less than 1% of this filtered load is excreted in the urine (approx. 140mEq/day). Because of the large filtered load of Na+ , small changes in Na+ reabsorption by the nephron can have a large effect on Na+ balance and thus the ECV (and volume of the ECF).

During euvolemia the collecting duct is the main nephron segment where Na+ reabsorption is adjusted to maintain excretion at a level appropriate for dietary intake. The reabsorptive capacity of the collecting duct is limited, so the other portions of the nephron must reabsorb the bulk of the filtered load of Na+ . During euvolemia, Na+ handling of the nephron can be explained by two general processes:

  1. Na+ reabsorption by the proximal tubule, Henle’s loop, and the distal tubule is regulated so that a relatively constant portion of the filtered load of Na+ is delivered to the collecting duct.
  2. Reabsorption of Na+ by the collecting duct is regulated so that the amount of Na+ excreted in the urine matches the amount ingested in the diet.

About two thirds (67%) of the filtered load of Na+ is reabsorbed in the early proximal tubule. An additional 20 to 25% of the filtered Na+ is reabsorbed in Henle’s loop (esp. thick ascending limb).

Only about 8 to 13% of the daily total filtered load of Na+ actually makes it down to the late distal tubules and collecting ducts (still a considerable amount – 3,250 mEq). Most healthy people with a normal diet only excrete 150 mEq of Na+ into the urine. Reabsorption of most of this sodium will occur in the late distal tubules and collecting ducts under the influence of aldosterone. To summarize, the kidney controls the amount of sodium that gets out of the plasma and into the urine in two ways:

  1. Altering the GFR (and thus the filtered load of Na+ ).
  2. Altering the tubular reabsorption rates of Na+ .

Know the mechanisms whereby a change in the amount of Na+ retained in the plasma affects the amount of water retained in the plasma, and how this relationship affects mean systemic arterial pressure.

The two most important hormones involved in the regulation of total plasma Na+ and therefore plasma volume, are aldosterone and atrial natriuretic peptide (ANP). One of the major roles of aldosterone in renal function is to promote the reabsorption of Na+ and the secretion of K+ through the principal cells in the late distal tubules and collecting ducts of the kidney, which is very important when volume and/or blood pressure are low. Expansion of the ECF results in an appropriate increase in Na+ excretion and a decrease in aldosterone release.

ANP is also an important factor. It appears to have two major actions:

  1. It is a vasodilator, which lowers systemic blood pressure
  2. It increases urinary Na+ and water excretion

Also, the diminished activity of the renin-angiotensin-aldosterone cascade that is seen with volume expansion may be mediated in part by ANP.

Know the difference between effective circulating volume (ECV) and extracellular fluid (ECF) volume.

The ECV is not a measurable body fluid compartment, like the ECF. As stated by Dr. Johnson, it is a concept related to the "fullness" and "pressure" within the arterial tree. In other words, unlike ECF, which refers to the volume of fluid and solute in both the plasma as well as the interstitial fluid (ISF), ECV refers to the volume, or fullness within the arteries only, as well as the pressure within these arteries.

See ECV sensors, pg. 4 of Dr. Johnson’s handout (Regulation of Sodium and Effective Circulating Volume).

Be aware of the etiology of some clinical situations I will try to discuss in class, such as the syndrome of inappropriate ADH (SIADH), and primary and secondary hyperaldosteronism.

Syndrome of inappropriate ADH (SIADH)- Characterized by plasma ADH levels that are elevated above what would be expected on the basis of body fluid osmolality and blood volume and pressure. Individuals with SIADH retain water, and their body fluids become progressively hyposomotic. In addition, their urine is more hyperosmotic than expected based on the low body-fluid osmolality. SIADH can be caused by infections and neoplasms of the brain, drugs (i.e.antitumor drugs), pulmonary diseases, and carcinoma of the lung.
Primary Hyperaldosteronism- Usually manifested as a tumor in the Zona Glomerulosa, the tissue in the adrenal cortex which produces aldosterone. Characteristics include elevated plasma Na+ , high plasma and urinary aldosterone, hypertension due to excessive Na+ and water retention, alkalosis due to hypokalemia, decreased levels of angiotensin II and renin, and a decreased hematocrit and plasma oncotic pressure due to expansion of the ECF volume.
Secondary Hyperaldosteronism- The most common cause is diuretic therapy. Loop and thiazide diuretics promote excessive secretion of Na+ into the urine. Eventually, the secretion of aldosterone from the adrenal cortex is promoted to retain Na+ and try to bring volume back to normal.

 


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