Concentration and Dilution IV

Fourth Lecture on Urine Concentration and Dilution

Overview of the Lecture

Focus areas:

  - Production and release of Antidiuretic Hormone (ADH)

  - Control mechanisms influenced by plasma osmolarity

  - Pathophysiologic control of ADH release in response to blood volume changes

  - Pathological states of ADH activity

Antidiuretic Hormone (ADH) - Arginine Vasopressin (AVP)

Definition: ADH is a hormone that plays a crucial role in maintaining water balance in the body. It helps control how much water the kidneys save and how much is excreted as urine.
Major actions of ADH:

  - Creates medullary interstitial concentration gradient: The kidneys have different sections, and ADH helps make the inner part of the kidney more concentrated with salt, which is needed for proper water reabsorption.

  - Enhances urea recycling: Urea is a waste product from protein metabolism. ADH helps recycle urea in the kidney's inner medullary collecting duct, allowing the body to save more water by reabsorbing it back into the bloodstream.

  - Countercurrent mechanism: This term describes how water and salts move in opposite directions in different parts of the kidney loop, which is important for maintaining a concentration gradient that allows for better water reabsorption.

  - Increases water permeability in the collecting duct: ADH makes the walls of the collecting ducts in the kidneys more permeable to water. It achieves this by:

    - Binding to V2 receptors on principal cells of the collecting duct, which are specialized cells that help manage water flow.

    - Activating a pathway that leads to the insertion of aquaporin-2 channels, essentially tiny openings that allow water to move out of the urine and back into the blood.

    - This process allows water to passively move from the urine (lumen) into the surrounding area (interstitium), driven by the higher concentration of salt in the interstitium, promoting reabsorption.

Synthesis and Release of ADH

Location of synthesis:

  - ADH is produced in the hypothalamus, a region at the base of the brain, specifically in two areas:

    - Paraventricular nucleus

    - Superoptic nucleus
Mechanism of release:

- After being made in the hypothalamus, ADH travels down the axon (a long projection of a neuron) to the posterior pituitary gland, where it is released into the bloodstream.
Control of ADH production and release:

  - ADH release is stimulated by changes at the blood-brain barrier, which is a selective barrier that protects the brain. Certain neurons in:

    - Subfornical organ (SFO)

    - Median preoptic area (MPOA)

    - Organum vasculosum of the lamina terminalis (OVLT)

  - These areas sense changes in the body’s blood consistency (osmolarity) and fluid levels.
Physiologic stimulus for ADH release:

- An increase in plasma osmolarity (the concentration of particles in the blood), which indicates dehydration. When this happens, neurons in the SFO, MPOA, and OVLT shrink, triggering an increase in ADH production in the hypothalamus.

Plasma Osmolarity and ADH Release

Threshold for ADH release:

- The threshold for initiating ADH release is around 280 milliosmoles per kilogram of water (mOsm/kg). Whenever plasma osmolarity falls below this point, the release of ADH is suppressed, meaning the body won’t hold onto excess water.
Graded response:

- As plasma osmolarity increases above this threshold, ADH release ramps up. The body has a very sensitive system, responding even to small changes (as low as a 1% increase) in plasma osmolarity to stimulate more ADH secretion.

Pathophysiologic Control of ADH Release

Response to blood volume changes:

  - When blood volume decreases (such as during dehydration), this triggers the release of ADH. The body detects changes mainly through baroreceptors located in the carotid arch (around the neck area) that monitor blood pressure and volume.

  - Conditions that lead to ADH release can include:

    - Hemorrhage (significant blood loss, which leads to loss of water and solute).

    - Severe sweating (where the body loses more water than the salt it loses).
Sensitivity:

- This system of monitoring blood volume is less sensitive than the process that monitors osmolarity, needing about a 10% decrease in blood volume before ADH is released.
High concentrations of ADH can also lead to blood vessel constriction, which helps to preserve blood pressure during lowered blood volume.
Complementary signals:

- Both signals (increased plasma osmolarity and decreased blood volume) can stimulate ADH release during dehydration. However, when there’s a significant loss in blood volume and stable plasma osmolarity, the volume change serves as the main signal.

Influence of Volume Status on ADH Release

In euvolemic states (normal blood volume):

- The threshold for ADH release remains stable at around 280 mOsm/kg, but the body will respond more aggressively as osmolality rises to retain more water.
In volume-expanded states:

- The sensitivity of ADH is decreased, shifting the threshold to the right, meaning that higher osmolarity is needed to trigger ADH, leading to lesser water retention in the body.
In volume-contracted states:

- The threshold shifts to the left, meaning ADH is released even at lower plasma osmolarity, leading to increased uptake of water from urine back into circulation.

Factors Affecting ADH Activity and Disorders

Inputs from the brain:

- Emotional states like pain and fear can stimulate the release of ADH, showing that our body’s hormonal responses are influenced by our mental state.
Impaired ADH activity conditions:

  - Certain conditions affect how ADH works:

    - Alcohol inhibits the release of ADH, which leads to less water absorption by the kidneys, causing hangover symptoms like dehydration.

    - Diabetes insipidus (DI):

      - Central DI: This is where the brain does not produce enough ADH.
      - Symptoms include high urine output with very dilute urine (often described as insipid, meaning without flavor).

      - Nephrogenic DI: Here the kidneys do not respond to ADH even though it is being produced normally. This can happen due to defects in:

        - V2 receptors (where ADH binds)

        - Signaling mechanisms that usually follow the binding of ADH

        - Aquaporin-2 channels that move water out of urine.

      - Patients need to drink large quantities of water to avoid becoming dehydrated.

Excessive ADH Release Conditions

Low effective circulating volume:

- Conditions seen in septic shock can cause fluid to leak into tissues rather than stay in blood vessels, leading the body to perceive it as low blood volume and release ADH, which could worsen swelling (edema).
Syndrome of inappropriate ADH secretion (SIADH):

  - This is when ADH is released too much despite total body water levels. This can be caused by:

    - Brain tumors that affect hormone production

    - Head injury

    - Certain medications

    - Rapid onset of low sodium levels in blood, requiring treatment with V2 receptor antagonists to help regulate the body’s water levels more effectively.

Summary of Key Points

ADH is produced in the hypothalamus and released into the blood from the posterior pituitary. This makes it essential in controlling how much water our body retains.
Primary physiologic stimulus for ADH release is an increase in plasma osmolality due to dehydration, prompting the kidneys to conserve water by increasing ADH levels. This happens through a finely tuned graded response.
Volume depletion also signals the need for ADH release but is less sensitive compared to osmotic signals. In extreme cases, high levels of ADH can constrict blood vessels to help maintain blood pressure.
Disruptions in ADH function can lead to diabetes insipidus, requiring significant water intake to prevent dehydration and loss of important body fluids.
Excessive ADH release can arise in conditions like septic shock or SIADH, resulting in dangerous changes to sodium levels in the bloodstream, highlighting the body’s delicate balance regarding hormone regulation and fluid homeostasis.