Dibartola Chapter 3: Disorders of Sodium and Water: Hypernatremia and Hyponatremia

What determines the volume of ECF?

Total body sodium content

What determines the osmolality and sodium concentrations of ECF?

Water balance

What is sensed for osmoregulation?

Plasma osmolality

What is sensed for volume regulation?

Effective circulating volume

What are the sensors in osmoregulation?

Hypothalamic osmoreceptors

What are the sensors in volume regulation?

Carotid sinus

Aortic arch

Glomerular afferent arterioles

Cardiac atria

Large pulmonary vessels

What are the effectors of osmoregulation?

Vasopressin

Thirst

What are the effectors of volume regulation?

Renin angiotensin-aldosterone system

Sympathetic nervous system

Atrial natriuretic peptide

“Pressure natriuresis”

Antidiuretic hormone

What is affected by osmoregulation?

Water excretion

Water intake

What is affected by volume regulation?

Urine sodium excretion

Osmolality

The concentration of osmotically active particles in a solution

• Function only of the number of particles, not related to their molecular weight, size, shape or charge

• Number of particles of solute per kilogram of solvent

Osmolarity

The number of particles of solute per liter of solution

Hyperosmotic

Osmolality is greater than that of the reference solution (often plasma)

Hyposmotic

Osmolality is less than that of the reference solution

Isosmotic

Osmolality identical to that of the reference solution

Calculated Plasma Osmolality

BUN and glucose are converted from mg/dL to mmol/L by the conversion factors 2.8 and 18

Measured osmolality should not exceed the calculated osmolality by more than ____?

10 mOsm/kg

If it does an abnormal osmolal gap is present

• Occurs when an unmeasured solute is present in a large quantity in plasma (e.g. mannitol or metabolites of ethylene glycol) or when hyperlipemia or hyperproteinemia results in pseudohyponatremia

Specific Gravity

The ratio of the weight of a volume of liquid to the weight of an equal volume of distilled water

• Depends on the number of particles present in the solution as well as their molecular weight

Effective Osmolality

• A change in the concentration of permeant solutes (e.g. urea, ethanol) does not cause movement of water because these solutes are distributed equally throughout total body water (TBW)

• A change in the concentration of impermeant solutes (e.g. glucose, sodium) does cause movement of water because such solutes do not readily cross cell membranes

Tonicity

The ability of a solution to initiate water movement

• Dependent on the presence of impermeant solutes in the solution

• May be thought of as effect osmolality

Hypertonic

Solution with a concentration of impermeant solutes greater than another solution that it is separated from by a semipermeable membrane

Hypotonic

Solution with a concentration of impermeant solutes less than that of another solution

Isotonic

Solution with a concentration of impermeant solutes equal to that of the reference solution

Estimate of Tonicity or Effective Osmolality

P_osm = BUN/2.8

Diuresis

Urine flow that is greater than normal

Solute or Osmotic Diuresis

Increased urine flow caused by excessive amounts of nonreabsorbed solute within the renal tubules

• e.g. polyuria associated with diabetes mellitus, administration of mannitol

• During osmotic diuresis urine osmolality approaches plasma osmolality

Water Diuresis

Increased urine flow caused by decreased reabsorption of solute-free water in the collecting ducts

• e.g. polyuria associated with psychogenic polydipsia or diabetes insipidus

• During water diuresis, urine osmolality is less than plasma osmolality

Isosthenuria

Urine with an osmolality equal to that of plasma

Hyposthenuria

Urine with an osmolality less than that of plasma

Hypersthenuria or Baruria

Urine with an osmolality greater than that of plasma

Hypertonic Dehydration

Results from pure water loss and loss of hypotonic fluid, increases tonicity of remaining body fluid

Isotonic Dehydration

Results from loss of fluid with the same osmolality as that of ECF, no osmotic stimulus for water movement and the remaining body fluids are unchanged in tonicity

Hypotonic Dehydration

Results from loss of hypertonic fluid or loss of isotonic fluid with water replacement, remaining body fluids become hypotonic

Change in ECF Volume with Pure Water Loss

Small decrease

Change in Total Solute Concentration of ECF with Pure Water Loss

Small increase

Change in ICF Volume with Pure Water Loss

Small decrease

Change in Total Solute Concentration of ICF with Pure Water Loss

Small increase

Change in ECF Volume with Hypotonic Fluid Loss

Moderate decrease

Change in Total Solute Concentration of ECF with Hypotonic Fluid Loss

Very small increase

Change in ICF Volume with Hypotonic Fluid Loss

Very small decrease

Change in Total Solute Concentration of ICF with Hypotonic Fluid Loss

Very small increase

Change in ECF Volume with Isotonic Dehydration

Large decrease

Change in Total Solute Concentration with Isotonic Dehydration

Normal

Change in ICF Volume with Isotonic Dehdyration

Normal

Change in Total Solute Concentration of ICF with Isotonic Dehydration

Normal

Change in ECF Volume with Hypertonic Fluid Loss

Very large decrease

Chance in Total Solute Concentration of the ECF with Hypertonic Fluid Loss

Very small decrease

Change in the ICF Volume with Hypertonic Fluid Loss

Very small increase

Change in the Total Solute Concentration of the ICF with Hypertonic Fluid Loss

Very small decrease

Change in ECF Volume with Isotonic Fluid Loss with Water Replacement

Large decrease

Change in Total Solute Concentration of the ECF with Isotonic Fluid Loss with Water Replacement

Small decrease

Change in ICF Volume with Isotonic Fluid Loss with Water Replacement

Small increase

Change in Total Solute Concentration of the ICF with Isotonic Fluid Loss with Water Replacement

Small decrease

What is serum sodium concentration an indication of?

The amount of sodium relative to the amount of water in the ECF

• Provides no direct information about total body sodium content

What does hypernatremia imply?

• An increased serum sodium concentration (hypernatremia) implies hyperosmolality

  • Hypernatremia develops when water intake has been inadequate, when the lost fluid is hypotonic to ECF, or when an excessive amount of sodium has been ingested or administered parenterally

What does hyponatremia imply?

• A decreased serum sodium (hyponatremia) usually, but not always, implies hyposmolality

  • Hyponatremia develops when the patient is unable to excrete ingested water or when urinary and insensible fluid losses have a combined osmolality greater than that of ingested or parenterally administered fluids

How is sodium removed from tubular cells in the kidney?

• The metabolic energy for sodium transport in the kidney is required by Na+, K+ ATPase in the basolateral membranes of the tubular cells

  • This enzyme translocates sodium from the cytoplasm of the tubular cells to the peritubular interstitium and maintains a low intracellular concentration of sodium, which promotes sodium entry into the cell at the luminal surface

What percentage of the filtered load of sodium is reabsorbed in the proximal tubules

67%

Sodium Reabsorption in the Proximal Tubule

• In the early proximal tubule, sodium crosses the luminal membrane by cotransport with glucose, amino acids, and phosphate and in exchange for H+ ions via the luminal Na+ - H+ antiporter

• Reabsorption of water and sodium with HCO3- and other solutes in this segment of the nephron increases the Cl- concentration in tubular fluid and facilitates Cl- reabsorption later in the proximal tubule

• In the late proximal tubule, sodium is reabsorbed primarily with Cl-

  • The luminal Na+ - H+ antiporter works in parallel with a luminal Cl- anion- antiporter and the net effect is NaCl reabsorption

What % of the filtered load of sodium is reabsorbed in the loop of Henle

25%, primarily in the thick ascending limb

Reabsorption of Sodium in the Loop of Henle

• In the thin descending and ascending limbs of Henle's loop, sodium and Cl- are passively reabsorbed

• In the thick ascending limb sodium crosses the luminal membranes via the Na+ - H+ antiporter and by an Na+K+2Cl- cotransporter

  • Na+K+2Cl- cotransporter is the site of action of the loop diuretic furosemide and bumetanide

  • There is a strong electrochemical gradient for Na+ entry across the luminal membrane in this region

What % of the filtered load of sodium is reabsorbed in the distal convoluted tubule and the connecting segment?

5%

Sodium Reabsorption in the Distal Convoluted Tubule and Connecting Segment

• In the early distal tubule (up to the connecting segment), sodium crosses the luminal membrane by means of a Na+Cl- cotransporter

  • This contransporter is inhibited by the thiazide diuretics

What % of the filtered load of sodium is reabsorbed in the collecting ducts?

3%

Sodium Reabsorption in the Collecting Ducts

• This segment of the nephron is responsible for altering sodium reabsorption in response to dietary fluctuations

• In the late distal tubule (connecting segment) and collecting ducts, sodium enters passively through Na+ channels in the luminal membranes of the principal cells

  • This movement of Na+ generates a lumen-negative transepithelial potential difference that facilitates Cl- reabsorption

• The Na+ channel in the principal cells is blocked by the diuretic amiloride and triamterene

• One of the main effects of aldosterone is to increase the number of open luminal Na+ channels in the cortical collecting ducts, altering sodium reabsorption in response to change in dietary sodium intake

Effective Circulating Volume

Relative fullness of the circulating portion of the extracellular compartment as perceived by the body

Where are low-pressure mechanoreceptors (volume receptors) located?

The cardiac atria and pulmonary vessels

Where are high-pressure baroreceptors (pressure receptors) located?

The aortic arch and carotid sinus

Renal Regulation of Sodium Balance

• The juxtaglomerular apparatus responds to changes in perfusion pressure with changes in renin production and release

• Kidney is the primary efferent limb of sodium control

  • Regulates sodium balance by excreting an amount of sodium each day equal to that ingested

  • The two points of control for sodium balance in the kidney are glomerular filtration and tubular reabsorption

    • Autoregulation maintains renal blood flow and GFR relatively constant despite fluctuations in systemic arterial pressure so the filtered load of sodium is also kept relatively constant

Effects of Changes in GFR on Sodium Balance

• Slight changes in GFR have the potential to have drastic effects on sodium balance if the absolute amount of sodium reabsorbed by the tubules remains constant

• If spontaneous (primary) fluctuations in GFR occur, the absolute tubular reabsorption of filtered solutes changes in a similar direction

  • The fraction of the filtered load that is reabsorbed remains relatively constant despite spontaneous changes in GFR

    • Called glomerulotubular balance

• Much of the sodium in the proximal tubules is reabsorbed along with several other solutes (e.g. glucose, amino acids, phosphate, and bicarbonate)

  • A spontaneous increase in GFR increases the filtered load of all of these solutes and their increased concentration in the proximal tubule enhances sodium reabsorption

Role of Changes in Peritubular Capillary Hydrostatic and Oncotic Pressure in Glomerulotubular Balance

If GFR spontaneously increases without a change in renal plasma flow (RPF) (i.e. filtration fraction increases), the blood leaving the efferent arterioles has lower hydrostatic and higher oncotic pressure, favoring water and solute reabsorption in the proximal tubules

Contribution of Autoregulation to Glomerulotubular Balance

When renal perfusion pressure is increased, afferent arteriolar constriction prevents transmission of the increased hydrostatic pressure to the glomerular capillaries and minimizes any increase in GFR and filtered solute load

Effects of Ingestion of a Sodium Load

• Autoregulation also contributes to glomerulotubular balance

  • When renal perfusion pressure is increased afferent arteriolar constriction prevents transmission of the increased hydrostatic pressure to the glomerular capillaries and minimizes any increase in GFR and filtered solute load

• Ingestion of a sodium load causes thirst, water consumption, and expansion of ECF volume

  • These events lead to a compensatory (secondary) increase in GFR by increasing hydrostatic pressure and decreasing oncotic pressure in the glomerular capillaries

  • Increased stretching of the afferent arterioles decreases renin secretion (and ultimately angiotensin II production)

  • Volume expansion also causes increased atrial stretch, release of atrial natriuretic peptide, and natriuresis

What type of changes in GFR evoke glomerulotubular balance?

Glomerulotubular balance is evoked with spontaneous (primary) increases in GFR but not compensatory (secondary) increases in GFR

What is the action of aldosterone?

Changes in renal absorption of sodium in response to dietary fluctuations in sodium intake are mediated by aldosterone

Aldosterone increases sodium reabsorption by increasing the number and activity of open sodium channels in the luminal membranes of the principal cells in the collecting ducts

Where is aldosterone produced?

The zona glomerulosa of the adrenal cortex

What stimulates production and release of aldosterone?

Angiotensin II, hyperkalemia, and ACTH

What inhibits release of aldosterone?

Dopamine and atrial natriuretic peptide

Effects of Increased Sodium Intake on Peritubular Capillary Factors (Starling Forces)

Increased sodium intake leads to expansion of the ECF volume and compensatory increases in GFR and renal plasma flow (i.e. filtration fraction remains unchanged)

• This increases hydrostatic pressure and decreases oncotic pressure in the peritubular capillaries, reducing sodium and water reabsorption in the proximal tubules

Effects of Decreased Sodium Intake on Peritubular Capillary Factors (Starling Forces)

Decreased sodium intake leads to volume contraction

• RPF decreases more than GFR (filtration fraction increases)

• Results in decreased hydrostatic pressure and increased oncotic pressure in the peritubular capillaries and enhanced proximal tubular reabsorption

Effects of Catecholamines on the Efferent and Afferent Arterioles

Catecholamine-induced vasoconstriction usually affects the efferent more than the afferent arterioles

• The resultant increase in filtration fraction alters peritubular capillary hemodynamics to favor water and sodium reabsorption (decreased hydrostatic pressure and increased oncotic pressure)

Effects of Catecholamines on Sodium Reabsorption

Catecholamines directly stimulate proximal tubular sodium reabsorption through an a1-adrenergic effect and stimulate renin release from the granular cells of the juxtaglomerular apparatus through a B1-adrenergic effect

• The angiotensin II ultimately produced also stimulates proximal tubular sodium reabsorption

The direct effects of catecholamines on proximal tubular sodium reabsorption offset the tendency of the increase in systemic arterial pressure to cause natriuresis

What leads to production of angiotensin II?

Decreased perfusion pressure in the afferent arterioles increases renin release from the granular cells of the juxtaglomerular apparatus and initiates the events that result in production of angiotensin II

Effects of Angiotensin II

Angiotensin II-induced vasoconstriction causes efferent more than afferent arteriolar constriction

• Results in an increase in filtration fraction and changes in peritubular capillary Starling forces (decreased hydrostatic pressure and increased oncotic pressure) that facilitate proximal tubular reabsorption of sodium and water

Angiotensin II also directly stimulates the Na+H+ antiporter in the proximal tubules, which facilitates sodium reabsorption and stimulates secretion of aldosterone from the adrenal gland

Where is atrial natriuretic peptide produced?

ANP is synthesized and stored in atrial myocytes

What stimulates the release of ANP?

Released in response to atrial distension caused by volume expansion

Effects of ANP

Effects of ANP facilitate renal excretion of sodium

• Causes dilation of the afferent arterioles and constriction of the efferent arterioles, leading to a primary increase in GFR

• Relaxes mesangial cells, resulting in an increase in the glomerular surface area available for filtration

• Inhibits sodium reabsorption in the cortical and inner medullary collecting ducts and inhibits renin secretion, decreasing the production of angiotensin II

• Inhibits aldosterone secretion by adrenal zona glomerulosa

Pressure Natriuresis

Renal sodium excretion and water excretion are markedly increased when renal arterial pressure increases even slightly without a change in GFR

Mechanism appears entirely intrarenal

Stimuli for Release of Aldosterone

Angiotensin II

Hyperkalemia

Adrenocorticotropic hormone

Inhibitors of Release of Aldosterone

Dopamine

ANP

Major Effects of Aldosterone

Increased number and activity of luminal Na+ channels and basolateral Na+,K+ ATPase in principal cells of cortical collecting ducts

Stimuli for Release of Angiotensin II

Decreased renal perfusion pressure

Inhibitors of Angiotensin II Release

Increased renal perfusion pressure

Major Effects of Angiotensin II

Systemic vasoconstriction

Glomerular arteriolar vasoconstriction (efferent >afferent)

Stimulates proximal Na+ reabsorption

Stimulates aldosterone secretion

Stimuli for Release of Atrial Natriuretic Peptide (ANP)

Increased atrial stretch

Inhibitors of Release of Atrial Natriuretic Peptide (ANP)

Decreased atrial stretch

Major Effects of Atrial Natriuretic Peptide (ANP)

Inhibits Na+ reabsorption in parts of collection duct

Directly increases glomerular filtration rate

Stimuli for Release of Catecholamines

Decreased effective circulating volume

Inhibitors of Release of Catecholamines

Increased effective circulating volume

Major Effects of Catecholamines

Vasoconstriction

Glomerular arteriolar vasoconstriction (efferent > afferent)

Increase proximal tubular Na+ reabsorption

(a1 effect)

Stimulate renin release (B1 effect)