Renal Sodium and Water Regulation

Background Concepts

Fluid compartments

To understand renal sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia and water regulation, it is important to understand how water is normally distributed in the body.

Total body water Total body water Body Fluid Compartments ( TBW TBW Body Fluid Compartments):

• A percentage of lean LEAN Quality Measurement and Improvement body weight
• TBW TBW Body Fluid Compartments accounts for:
  • 60% of lean LEAN Quality Measurement and Improvement weight in men
  • 50% of lean LEAN Quality Measurement and Improvement weight in women

Intracellular fluid Intracellular fluid The fluid inside cells. Body Fluid Compartments ( ICF ICF The fluid inside cells. Body Fluid Compartments):

• All fluid enclosed within cells by their plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products membranes
• ⅔ of TBW TBW Body Fluid Compartments

Extracellular fluid Extracellular fluid The fluid of the body that is outside of cells. It is the external environment for the cells. Body Fluid Compartments (ECF): 

• All fluid outside the cells
• ⅓ of TBW TBW Body Fluid Compartments
• Divided into 2 sub-compartments:
  • Intravascular fluid Intravascular fluid Body Fluid Compartments:
    • The fluid component of blood (also known as plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products)
    • ¼ of the ECF
    • Approximately 8% of the TBW TBW Body Fluid Compartments (⅓ x ¼)
  • Interstitial fluid Interstitial fluid Body Fluid Compartments:
    • The fluid that surrounds cells that are not within the blood
    • ¾ of the ECF
    • Approximately 25% of the TBW TBW Body Fluid Compartments (⅓ x ¾)

Osmolality

Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality refers to the combined concentration of all solutes in the blood.

• Determinants of plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality:
  • Mostly determined by serum Na⁺ (sNa⁺)
  • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance and BUN contribute, but to a much smaller degree when in the normal range.
  • All other solutes contribute only a negligible amount → not included in formula
• Equation: Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality = (2 x sNa⁺) + ( glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance/18) + (BUN/2.8)
• Normal range: 275–295 mOsm/kg H₂O
• Regulation:
  • Osmoreceptors in the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus sense osmolality.
  • Important for water regulation

Tonicity

Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products tonicity refers to the concentration of only the osmotically active Osmotically Active Osmotic Diuretics solutes in blood and is often referred to as effective osmolality.

• Osmotically active Osmotically Active Osmotic Diuretics solutes:
  • Do not equilibrate across a semipermeable membrane Semipermeable membrane Peritoneal Dialysis and Hemodialysis (these solutes cannot move freely across cell membranes)
  • Difference in concentrations on each side of membrane → creates an osmotic force
  • These solutes are called “effective osmoles.”
• Non-osmotically active solutes:
  • Do equilibrate across a semipermeable membrane Semipermeable membrane Peritoneal Dialysis and Hemodialysis (these solutes can move freely across cell membranes)
  • Equal concentrations on each side of membrane → no osmotic force
  • These solutes are called “ineffective osmoles.”
• Equation: effective plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality = (2 x sNa⁺) + ( glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance/18)
  • Na⁺ and glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance are effective osmoles:
    • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products tonicity is mostly determined by sNa⁺.
    • Normal glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance concentrations do not contribute much to tonicity.
  • Urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle (e.g., BUN) is an ineffective osmole → not considered for the tonicity equation 
  • Other effective osmoles contribute only a negligible amount → not included in the formula
• Regulation:
  • Osmoreceptors in the kidney sense tonicity.
  • Important for Na⁺ regulation
• Tonicity determines how water shifts between the body’s fluid compartments.
• Compared to normal plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products, a fluid may be:
  • Hypertonic: containing more osmotically active Osmotically Active Osmotic Diuretics solutes in the fluid 
  • Isotonic: containing the same amount of osmotically active Osmotically Active Osmotic Diuretics solutes in the fluid
  • Hypotonic: less osmotically active Osmotically Active Osmotic Diuretics solutes in the fluid
• Tonicity can be discordant with plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality:
  • Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome → elevated BUN → ↑ plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality but normal tonicity
  • Ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism intoxication (ineffective osmole) → ↑ plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality but normal tonicity

Disorders of water balance

• Total Na⁺ in the body determines the ECF volume:
  • Hypovolemia Hypovolemia Sepsis in Children: volume is depleted → ↓ total body Na⁺
  • Hypervolemia: volume overloaded → ↑ total body Na⁺
  • Assessed on physical exam, and not sNa⁺ levels
• Disorders of water balance are characterized by abnormalities in the concentration of sNa⁺:
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia: too much water
  • Hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia: too little water
  • Both disorders can exist at any level of total body Na⁺.

Renal Sodium and Water Handling

A nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy is the functional unit of the kidney through which fluid and solutes, including Na⁺, are filtered, reabsorbed, and secreted.

Glomerulus and proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System

• Glomerulus: Water and Na⁺ are freely filtered.
• Proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System:
  • Approximately ⅔ of filtered water and Na⁺ are reabsorbed.
  • Tubular fluid is isotonic to plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products.

Thick ascending limb of the loop of Henle Loop of Henle The U-shaped portion of the renal tubule in the kidney medulla, consisting of a descending limb and an ascending limb. It is situated between the proximal kidney tubule and the distal kidney tubule. Tubular System (TAL)

• Location of the sodium-potassium-chloride cotransporter 2 ( NKCC2 NKCC2 Renal Potassium Regulation cotransporter)
  • Na⁺, K⁺, and Cl^– are reabsorbed.
  • TAL is not permeable to water.
  • Water does not follow solutes (Na⁺, K⁺, Cl^–) into the medulla.
  • Generates an osmotic gradient between the tubular fluid and renal medulla 
• Tubular fluid is hypotonic to plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products.
• Known as a “diluting segment” (urine is diluted)

Distal convoluted tubule Distal convoluted tubule The portion of renal tubule that begins from the enlarged segment of the ascending limb of the loop of henle. It reenters the kidney cortex and forms the convoluted segments of the distal tubule. Gitelman Syndrome (DCT)

• Location of thiazide-sensitive NaCl cotransporter NaCl cotransporter A subclass of symporters found in kidney tubules, distal that are the major pathway for salt resorption. Inhibition of these symporters by benzothiadiazine is the basis of action of some diuretics. Tubular System
  • Na⁺ and Cl^– are reabsorbed.
  • DCT is not permeable to water.
  • Water does not follow solutes (Na⁺, Cl^–) into the medulla.
  • Generates an even stronger osmotic gradient between the tubular fluid and renal medulla 
• Tubular fluid is even more hypotonic to plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products at this point.
• Another “diluting segment”

Collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma

• The segment primarily responsible for maintaining plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality by concentrating or diluting the urine
• Contains the aquaporin channels Channels The Cell: Cell Membrane:
  • Allow water to move from the tubular fluid into renal medulla by diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis
  • Renal medulla is hypertonic due to solute reabsorption in the diluting segments (TAL and DCT).
• Antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia (ADH) stimulates the production and insertion of aquaporins Aquaporins A class of porins that allow the passage of water and other small molecules across cell membranes. Tubular System
  • ↑ ADH levels → ↑ aquaporins Aquaporins A class of porins that allow the passage of water and other small molecules across cell membranes. Tubular System → ↑ water reabsorption → concentrated urine
  • ↓ ADH levels → ↓ aquaporins Aquaporins A class of porins that allow the passage of water and other small molecules across cell membranes. Tubular System → ↓ water reabsorption → dilute urine

Sodium Regulation

Overview

The body regulates Na⁺ balance by sensing changes in the effective circulating volume ( ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition), which is also known as the effective arterial blood volume (EABV).

• The ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition is the portion of the intravascular volume that is found on the arterial side only.
• Changes in Na⁺ balance result in changes in the ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition.
• Changes in the ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition are relayed to the kidney primarily through:
  • The RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones 
  • Natriuretic peptides Natriuretic peptides Peptides that regulate the water-electrolyte balance in the body, also known as natriuretic peptide hormones. Several have been sequenced (atrial natriuretic factor; brain natriuretic peptide; c-type natriuretic peptide). Arterial Pressure Regulation

Renin-angiotensin-aldosterone system Renin-angiotensin-aldosterone system A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones

The RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones is stimulated by a low ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition:

• Juxtaglomerular apparatus and carotid sinus Carotid sinus The dilated portion of the common carotid artery at its bifurcation into external and internal carotids. It contains baroreceptors which, when stimulated, cause slowing of the heart, vasodilatation, and a fall in blood pressure. Carotid Arterial System: Anatomy/ aortic arch Aortic arch Mediastinum and Great Vessels: Anatomy baroreceptors Baroreceptors Receptors in the vascular system, particularly the aorta and carotid sinus, which are sensitive to stretch of the vessel walls. Diabetes Insipidus trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation renin release from kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy when ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition is ↓
• Renin ( kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy) → converts angiotensinogen ( liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy) to angiotensin I 
• ACE ( lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy) → converts angiotensin I to angiotensin II
• Angiotensin II:
  • Causes vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure
  • Stimulates aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia release (from the adrenal cortex Adrenal Cortex The outer layer of the adrenal gland. It is derived from mesoderm and comprised of three zones (outer zona glomerulosa, middle zona fasciculata, and inner zona reticularis) with each producing various steroids preferentially, such as aldosterone; hydrocortisone; dehydroepiandrosterone; and androstenedione. Adrenal cortex function is regulated by pituitary adrenocorticotropin. Adrenal Glands: Anatomy)

Effects of aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia:

• Stimulates production of the following proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis within the principal cells Principal cells Tubular System in the collecting ducts:
  • Na⁺/K⁺-ATPase on the basolateral side
  • Epithelial sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia channels Channels The Cell: Cell Membrane ( ENaC ENaC Sodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure. Liddle Syndrome) on the lumen side: allow Na⁺ reabsorption from the lumen into the principal cells Principal cells Tubular System
  • Renal outer medullary potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia (ROMK) channels Channels The Cell: Cell Membrane on the lumen side: allow excretion of K⁺ into the urine
• Stimulates Na⁺ reabsorption from the renal tubules
  • Water follows the Na⁺.
  • Creates a negative electrical gradient Electrical gradient Renal Potassium Regulation across the lumen promoting the secretion Secretion Coagulation Studies of K⁺ and H⁺ into the urine
• End result of ↑ aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia: 
  • ↑ Serum Na⁺ (↓ urinary excretion of Na⁺)
  • ↑ BP (↑ water reabsorption from the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy)
  • ↓ Serum K⁺ (↑ urinary excretion of K⁺)
  • ↑ Serum pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance (↑ urinary excretion of H⁺)

Natriuretic peptides Natriuretic peptides Peptides that regulate the water-electrolyte balance in the body, also known as natriuretic peptide hormones. Several have been sequenced (atrial natriuretic factor; brain natriuretic peptide; c-type natriuretic peptide). Arterial Pressure Regulation

• Natriuretic peptides Natriuretic peptides Peptides that regulate the water-electrolyte balance in the body, also known as natriuretic peptide hormones. Several have been sequenced (atrial natriuretic factor; brain natriuretic peptide; c-type natriuretic peptide). Arterial Pressure Regulation include:
  • Atrial natriuretic peptide (ANP)
  • BNP
• Regulation: 
  • Cardiac baroreceptors Baroreceptors Receptors in the vascular system, particularly the aorta and carotid sinus, which are sensitive to stretch of the vessel walls. Diabetes Insipidus sense an ↑ in ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition
  • Trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation the release of natriuretic peptides Natriuretic peptides Peptides that regulate the water-electrolyte balance in the body, also known as natriuretic peptide hormones. Several have been sequenced (atrial natriuretic factor; brain natriuretic peptide; c-type natriuretic peptide). Arterial Pressure Regulation from the atria and ventricles
• Functions of the natriuretic peptides:
  • Stimulate urinary Na⁺ excretion (known as “natriuresis”)
  • Water follows the Na⁺.
  • ANP also has counterregulatory actions to inhibit the RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones.

Summary

Changes in ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition are sensed by the juxtaglomerular apparatus, carotid-sinus and aortic-arch baroreceptors Baroreceptors Receptors in the vascular system, particularly the aorta and carotid sinus, which are sensitive to stretch of the vessel walls. Diabetes Insipidus, and cardiac baroreceptors Baroreceptors Receptors in the vascular system, particularly the aorta and carotid sinus, which are sensitive to stretch of the vessel walls. Diabetes Insipidus.

• ↑ Na⁺ causes ↑ ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition (↑ stretch), which results in:
  • ↓ Renin release
  • ↑ Natriuretic peptide release
  • End result: ↑ Na⁺ and water excretion
• ↓ Na⁺ causes ↓ ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition (↓ stretch), which results in:
  • ↑ Renin release
  • ↓ Natriuretic peptide release
  • End result: ↑ Na⁺ and water retention

Water Regulation

Overview

• To excrete water, the urine is diluted, which requires:
  • Solute and fluid delivery to the kidney
  • Functioning diluting segments
  • Suppressed ADH
• To retain free water, the urine is concentrated, which requires:
  • ↑ Solute reabsorption in the thick ascending loop
  • Presence of ADH
  • Ability of collecting ducts to respond to ADH by inserting aquaporin channels Channels The Cell: Cell Membrane
• ADH can be released in response to osmotic and non-osmotic regulation.

Osmotic ADH regulation

Water regulation is primarily controlled by osmoreceptors in the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus, which maintain plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality very tightly. Very small changes in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality result in changes in ADH release and the sensation of thirst.

• Osmoreceptors:
  • Located in the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus
  • Detect changes in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality (caused by changes in water balance)
• ↑ Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality sensed by the hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus triggers:
  • ADH release from the posterior pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types
  • Thirst
• ADH binds to:
  • V₂ receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors on the basolateral membrane of collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma cells → stimulate insertion of aquaporin channels Channels The Cell: Cell Membrane into the apical membrane
  • V_1A receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors in vasculature → cause vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure
• Overall effect:
  • ↑ Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality → ↑ ADH → ↑ aquaporins Aquaporins A class of porins that allow the passage of water and other small molecules across cell membranes. Tubular System → ↑ water reabsorption
  • ↓ Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality → ↓ ADH → ↓ aquaporins Aquaporins A class of porins that allow the passage of water and other small molecules across cell membranes. Tubular System → ↑ water excretion
• Normal ADH levels:
  • Usually minimal when plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality is in the normal range
  • ADH secretion Secretion Coagulation Studies increases linearly when plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality is elevated.

Non-osmotic ADH release

Very large decreases in the ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition can independently cause ADH release in an attempt to preserve volume.

• Can occur even if plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products tonicity is not elevated 
• Occurs only in extreme settings, where ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition losses are high enough to cause hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension:
  • Acute severe bleeding
  • Severe diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
• Constitutes a salvage mechanism: 
  • The body reabsorbs as much water as possible to support the BP when other mechanisms (e.g., RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones) are not sufficient.
  • ↓ Volume will supersede a ↓ in osmolality: If the volume is low enough, ADH will be released even if the patient is already hypoosmotic. 
• ↓ ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition is sensed by:
  • Macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy densa cells 
  • Renal afferent Afferent Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology arterioles Arterioles The smallest divisions of the arteries located between the muscular arteries and the capillaries. Arteries: Histology
  • Atrial and carotid sinus Carotid sinus The dilated portion of the common carotid artery at its bifurcation into external and internal carotids. It contains baroreceptors which, when stimulated, cause slowing of the heart, vasodilatation, and a fall in blood pressure. Carotid Arterial System: Anatomy baroreceptors Baroreceptors Receptors in the vascular system, particularly the aorta and carotid sinus, which are sensitive to stretch of the vessel walls. Diabetes Insipidus
• ↓ ECV ECV A procedure in which the physician attempts to manually rotate the fetus from a breech to a cephalic presentation by pushing on the maternal abdomen Fetal Malpresentation and Malposition triggers:
  • Activation of the RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones
  • Norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS release
  • ANP Suppression Suppression Defense Mechanisms
  • ADH release
• End effect:
  • Vasoconstriction Vasoconstriction The physiological narrowing of blood vessels by contraction of the vascular smooth muscle. Vascular Resistance, Flow, and Mean Arterial Pressure
  • ↑ Volume

Clinical Relevance

• Hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia: elevated sNa⁺ concentration, defined as Na⁺ levels > 145 mmol/L. The pathophysiology most commonly involves a lack of access to water (e.g., altered mental status Altered Mental Status Sepsis in Children, dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders, mechanically ventilated patient). Another important etiology is diabetes insipidus Diabetes Insipidus Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of DI: central DI (CDI) and nephrogenic DI (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus ( DI DI Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus). Mild hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia is characterized by an increased sensation of thirst, whereas more severe hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia can result in altered mental status Altered Mental Status Sepsis in Children. The etiology of hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia is often easy to determine based on clinical history. Treatment primarily involves replacement of the free water deficit.
• DI DI Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus: a cause of hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia due to increased urinary losses of water. Diabetes insipidus Diabetes Insipidus Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of DI: central DI (CDI) and nephrogenic DI (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus can be either central, due to decreased release of ADH, or nephrogenic, due to renal resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing to ADH. Without effective ADH, water cannot be effectively absorbed in the collecting ducts, leading to impaired urinary concentration and inappropriately dilute urine. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will present with polyuria Polyuria Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. Renal Potassium Regulation, nocturia Nocturia Frequent urination at night that interrupts sleep. It is often associated with outflow obstruction, diabetes mellitus, or bladder inflammation (cystitis). Diabetes Insipidus, polydipsia Polydipsia Excessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin. Diabetes Insipidus, hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia, and increased osmolality. Management may include desmopressin Desmopressin Hemophilia (for central DI Central DI A genetic or acquired polyuric disorder caused by a deficiency of vasopressins secreted by the neurohypophysis. Clinical signs include the excretion of large volumes of dilute urine; hypernatremia; thirst; and polydipsia. Etiologies include head trauma; surgeries and diseases involving the hypothalamus and the pituitary gland. This disorder may also be caused by mutations of genes such as arvp encoding vasopressin and its corresponding neurophysin (neurophysins). Diabetes Insipidus), a low-Na⁺/low-protein diet, diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication, and NSAIDs NSAIDS Primary vs Secondary Headaches.
• Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia: decreased sNa⁺ concentration, defined as Na⁺ levels < 135 mmol/L. The pathophysiology is more varied than hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia, but most commonly involves a dilution of the total body Na⁺ due to an increase in the total body water Total body water Body Fluid Compartments. The clinical presentation varies greatly from asymptomatic to subtle cognitive deficits to seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures and death. Treatment is guided by acuity and severity of symptoms, and usually involves a combination of oral fluid restriction and hypertonic IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids. Overly rapid correction of hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia can lead to an irreversible neurological complication known as the osmotic demyelination Demyelination Multiple Sclerosis syndrome.
• Hypervolemia: an increase in ECF volume that occurs due to an increase in total body Na⁺. Clinical presentation includes hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, pulmonary edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites, pitting edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema in the lower extremities, and weight gain. Common etiologies include congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, and renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome. In these diseases, the mechanisms of Na⁺ regulation are disturbed and the increased total body Na⁺ is not excreted. Treatment is with loop diuretics Loop diuretics Loop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent. Loop Diuretics, which results in increased urinary Na⁺ and water losses.
• Hypovolemia Hypovolemia Sepsis in Children: a decrease in ECF volume that occurs due to a decrease in total body Na⁺. Clinical presentation includes hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, decreased skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions turgor, dry mucous membranes, orthostatic vital signs, and weight loss Weight loss Decrease in existing body weight. Bariatric Surgery. Common etiologies include diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, diuretic use, bleeding, poor oral intake, and 3rd spacing of fluids. Treatment includes administration of isotonic IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids, such as 0.9% NaCl or packed RBCs Packed RBCs Transfusion Products.