Osmoregulation and the Control of

ICF Volume
 Clinical relevance
• Abnormal plasma osmolality is a common electrolyte
disorder encountered in medicine.
– Occurs in ~5-7% of hospitalized patients (~30% in
elderly)

• Both the osmotic disturbance itself, as well as its

treatment can have life-threatening consequences.

• Proper treatment requires an understanding of the

mechanisms of water balance and the role of the kidney.
 Plasma Osmolality (Posm)

• A measure of the “concentration” of the plasma

[osmoles per kilogram of water (mOsm/KgH2O)]

• Provides Osmotic Pressure, which dictates movement

of water via osmosis

• Osmolality of all fluid compartments is essentially

equal, so we can use plasma osmolality to estimate
osmolality of the total body water
• This is the parameter that is sensed and tightly
regulated to maintain water balance
 Plasma Osmolality (Posm)
• Major plasma solutes are sodium and its accompanying
anions, but there are also smaller but significant
contributions by glucose and urea

• Posm can be estimatedCALCULATED as:

+ [glucose] BUN
Posm = 2 [Na ]+ +
18 2.8
• Normal range is 275-290 mOsm/kgH2O
 Plasma Osmolality (Posm)
• Osmolality can also be "measured" via freezing point
depression

• The difference between measured vs. calculated osmolality

is called an "osmolar gap". Usually <10mOsm/Kg

• Elevated osmolar gap suggests accumulation of

unmeasured osmoles (eg; ethyl alcohol, triacylglycerides etc)
 Why need to regulate [Na] and
Plasma osmolality?

• Extracellular Osm = Intracellular Osm = Body fluid Osm

• Cells are permeable to water and will be affected by
changes in [Na]/plasma osmolality.
Effects of changes in osmolality
on cell physiology

270 285 310

mOsm/kg mOsm/kg mOsm/kg
 Regulation of plasma osmolality
(Osmoregulation)

• Sensors – Osmoreceptors (hypothalamus)

• Effectors – ADH and Thirst
 Antidiuretic hormone (ADH)
• Human form = Arginine
vasopressin (AVP)

• 9 amino acid peptide

produced by neuroendocrine
cells in supraoptic and
paraventricular nuclei of
the hypothalamus

• Packaged in granules,
transported down axons, and
stored in nerve terminals
located in the posterior
pituitary

• Acts on collecting ducts to

regulate water
reabsorption
Mechanism of ADH in Principle Cells
 Actions of ADH
• The absence or presence of ADH is the major
physiologic determinant of urinary water excretion or
retention.

• Actions of ADH in the kidney (V2 receptors):

1. Increases permeability of the collecting ducts to water
2. Increases permeability of the medullary collecting ducts to
urea
3. Stimulates reabsorption of NaCl by the thick ascending
limb (TAL) and K+ secretion by the collecting ducts

• Actions of ADH on the vasculature (V1 receptors):

– Induces vasoconstriction (hence the name "vasopressin")
 Thirst Mechanism
• Increase in plasma osmolality or
decrease in volume stimulates
thirst

• Osmotic threshold for triggering thirst

is higher than that for ADH secretion
(295 vs 285 mOsm/kg)

• “Thirst center” is located in same

region of hypothalamus as region
involved with ADH secretion

• Sensation of thirst is satisfied by the

Valtin H Am J Physiol Regul Integr
act of drinking, even before enough Comp Physiol 2002
water has been absorbed from the
GI tract to correct Posm
The response to changes in osmolality
285 mOsm/kg

Addition of water 250 mOsm/kg 320 mOsm/kg Loss of water

Hypothalamic Hypothalamic
osmoreceptors osmoreceptors

ADH OFF Thirst ADH ON

Dilute urine Concentrated urine

Water excreted Minimize further loss

Plasma osmolality Minimize further rise in

increased back towards plasma osmolality
normal
 H2O balance

Thirst (input) ADH (renal output)

 Disorders of Water Balance
• Water excess = associated with hypo-osm.
Water deficit = associated with hyper-osm.

• These disorders are detected on the basis of

abnormally low or high Na+ (and sometimes
glucose etc) concentration in the blood

• Classic disorders:
– Hyponatremia = low plasma [Na+]
– Hypernatremia = high plasma [Na+]
 Hyponatremia
• Plasma [Na+] < 135 mEq/L (normal 136-145)

• Associated with hypo-osmolality

• Theoretically can result from either:

– Loss of Na+
– Increase in total body water (retention of ingested or infused
water)

• The most common cause of hyponatremia is

abnormal water retention that leads to excess water in
relation to solute

• Eg; Pure water gain (SIADH, primary polydipsia)

Gain of hypotonic water (hypotonic correction of diarrhoea)
 Causes of Hyponatremia:
Syndrome of Inappropriate ADH secretion (SIADH)

Causes:
• CNS disturbances (meningitis, head injury etc)
• Ectopic ADH production (tumors e.g. small cell
carcinoma of the lung)
• Drugs (therapeutics and designers e.g. opioids, ecstasy)
• Pulmonary disease (pneumonia)
• Hereditary SIADH (mirror image of nephrogenic DI due
to gain of function mutation in the V2 receptor)
• Major surgery (ADH secretion triggered by pain, nausea
and narcotics)
• Hypothyroidism
Pathological settings where ADH is “appropriately”
elevated (due to Angiotensin-II activation)

True extracellular volume depletion > 10%

• Hemorhagic shock
• Diarrhoea/vomiting etc

Note: ADH may also be elevated due to Ang-II activation in the

setting of "perceived" volume depletion where "effective
circulating volume" is low but total ECF volume is normal or
even elevated.
• Heart failure
• Liver cirrhosis
• Nephrotic syndrome
• Sepsis, anaphylaxis etc
 Cell volume: Hypotonicity

Hyponatremia
Solute and water

Normal Initial Adaptation

Swelling happens quickly (and is mechanism of ADH

and Thirst reduction), but if excessive and not controlled
leads to neurologic dysfuntion. Cells adapt “osmoregulate” by
decreasing solute in the cells (K and organics). Cell specific
mechanisms: may be complete in 24 hrs.
Symptoms of (acute) hyponatremia
Anorexia, nausea, headache, lethargy,
apathy, disorientation, agitation,
hyper>hypo>areflexia , focal neurologic
Salivation ⇑ deficits, seizures, coma
Hypoventilation,
Cheyne-Stokes respiration,
pulmonary edema Bradycardia
BP ⇑
Twitching

Polyuria/Oliguria
(Mostly Oliguria in SIADH
[with high urine osmolality]
etc. Polyuria may occur in
primary polydipsia)
 Treatment of Hyponatremia

• Consider chronicity (acute - 48hr - chronic)

• Consider symptoms
• Consider severity
• Consider volume status
 Treatment of Hyponatremia

• Mild/asymptomatic
- Acute
- Chronic

~ Fluid restriction
~ Vaptan (ADH receptor antagonist)

Note: IV fluids are reserved for severe/symptomatic hyponatremia or

in hyponatremia associated with volume deficit.
 IVF for Hyponatremia

Sterile water D5W ½ NS Normal Saline 3% saline

5% Dextrose 0.45% NaCl 0.9% NaCl

In water
Na+ = 77Meq/L Na+ = 154 514 mEq/L
mEq/L
hypotonic Hypotonic hypotonic isotonic hypertonic
but
isoosmotic

Options: D5 NS, D5 ½ NS, NS, 3% Saline

 Treatment of Hyponatremia
• Severe/symptomatic
- Acute (seizure, coma etc)
~ Hypertonic saline (3%)
~ Loop diuretics with NS (0.9%)
~ Fluid restriction + Vaptan
- Chronic
~ D5NS vs. D5-halfNS
~ Fluid restriction + Vaptan
 Treatment of Hyponatremia
• Severe/symptomatic

- Correct Na+ SLOWLY. No more than

12mEq/L in 24 hours, esp. if chronic
(risk of osmotic demyelination upon
rapid correction).
Central Pontine Myelinosis

Clinically: Flaccid paralysis, dysarthria, dysphagia.

High mortality
Hyponatremia associated with
Volume Disturbance
Usually simple hyponatremia is due to water
excess relative to solutes, not accompanied
with volume disturbance (euvolemic)

In co-existing volume disturbance, volume

abnormalities take precedence over osmolar
disturbances
Hyponatremia associated with
Volume Disturbance
• Hypervolemic - Loop diuretics + Na, vaptan

• Euvolemic - Fluid restriction, vaptan

• Hypovolemic - IV fluids.
Correct volume deficit first with NS,
then Na+ deficit with D5NS, D5½NS.
 IV Fluids for Rx of Hypovolemic
Hyponatremia
• Correction of hypovolemia by NS removes the
stimulus for ADH (A-II) causing H2O diuresis,
hence rapid correction of hyponatremia. Thus,
switch to D5NS or D5-halfNS once BP is stable.

• Important - Treat underlying conditions as well

eg; meningitis, pneumonia, lung cancer,
withdraw opioids and other meds etc
 Key Concepts

• Hyponatremia is mostly due to excessive

water retention relative to solutes.

• Long standing hyponatremia (>48hrs) should

be corrected slowly to avoid the risk of
osmotic demyelination.

• Volume abnormalities take precedence over

osmolar disturbances.
 Hypernatremia
• Plasma [Na+] > 146 mEq/L (normal 136-145)

• Associated with hyperosmolality

• Theoretically can result from either:
– Administration/ingestion of hypertonic fluids (too much sodium)
– Increased water losses

• An increase in plasma osmolality activates ADH secretion and

thirst mechanisms, which promote water retention and
increase water intake

• Therefore, hypernatremia mostly occurs due to impaired

ADH function or thirst mechanism.
• Eg; Loss of pure water (Diabetes insipidus, hypodipsia)
Loss of hypotonic water (Excessive sweating, loop diuretics)
Impaired thirst/access to water (critically ill, elderly patients)
 Causes of Hypernatremia:
Diabetes insipidus

Central DI = inadequate Nephrogenic DI = the

release of ADH kidney is resistant to ADH
Causes: Causes:
• Genetic defect (rare) •Familial
• Damage of the hypothalamus or •X-LINKED (V2 receptor mutation)
pituitary stalk (head trauma, •Autosomal (mutant aquaporin-2)
tumor, aneurysm) •Secondary to:
•Hypokalemia
•Hypercalcemia
•Renal disease
•Drugs
•Lithium
 Cell volume: Hypertonicity

Hypernatremia
Solute and water

Normal Initial Adaptation

Shrinking happens quickly (and is mechanism of ADH
and Thirst stimulation), but if excessive and not controlled
leads to neurologic dysfuntion. Cells adapt“osmoregulate” by
increasing solute in the cells by synthesis or uptake of
(osmolytes) including K and organics like amines (taurine
betaine), glycerophosphocholine, polyols (sorbitol, inositol)
amino acids (glutamine). Cell specific mechanisms: may be
complete in 24 hrs.
Symptoms of (acute) hypernatremia
Restlessness, weakness, seizures,
Brain hemorrhage delirium, maniacal behavior, coma

Lacrimation ⇓ Fever
Thirst
Salivation ⇓ Dry, sticky mucus membranes
Swollen tongue
Hyperventilation
BP ⇓ Tachycardia

Tissue turgor ⇓

Flushed dry skin

Polyuria/Oliguria
(Polyuria if DI is the
cause. Oliguria if water
deficient.)
 Treatment of HypHUnatremia

• Mild/asymptomatic
- Acute
- Chronic

~ Free water access (orally)

 Treatment of HypHUnatremia
• Severe/symptomatic
- Acute
- Chronic

~ IV D5W
~ Free water access (orally)
 Treatment of HypHUnatremia
• Severe/symptomatic

- Correct Na+ SLOWLY. No more than

12mEq/L in 24 hours, esp. if chronic
(risk of cerebral edema upon rapid
correction).
HypHUnatremia associated with
Volume Disturbance
• Hypervolemic - Loop diuretics WITH free
water boluses (carefully)

• Euvolemic - Free water access

• Hypovolemic - IV fluids.
Correct volume deficit first with NS,
then water deficit with D5%.
 Summary on Rx of Hypernatremia

• Replace water losses

– Water orally (asymptomatic/mild)
– Intravenous (as 5% dextrose in water in symptomatic/severe)

• Replace both the existing water deficit and any

ongoing water losses (insensible, renal etc ~1.5L/d)

• Treat underlying condition (eg; desmopressin in centr.

DI, treat hypokalemia/hypercalcemia in nephrog. DI)
 Key Concepts

• Hypernatremia commonly occurs due to

impairment of ADH secretion/function or
thirst mechanism.

• Long standing hypernatremia should be treated

slowly to avoid the risk of cerebral edema.
 Clinical Scenario I

• A 88 years old patient has had fever (4

days) goes into coma. Na 175 meq/L

- What is the expected urine osmolality?

- ADH?
 Clinical Scenario I
• Loss of water through sweat due to fever.
Unreplaced water, unable to
access water  hypernatremia, coma.
• ADH should be high, urine concentrated.

- Should patient be corrected immediately

to Na 140?
 Clinical Scenario I
• No, slowly because of adaptations that have
corrected cell volume. Rapid water infusion
will cause cerebral edema.
• Best to correct at about 10-12 meq/L per day
 Clinical Scenario II
16 year old patient has a hx of enuresis,
increasing polydipsia and polyuria. No head
trauma, no abnormal neurologic signs.
Na 144 meq/l , glucose 75 mg/dl
Uosm 50 mosm/kg; urine volume 9 liters/day

- What diagnostic procedures would

distinguish between potential causes?
 Clinical Scenario II
• The high normal Na with max dilute urine
already is suspicious for DI.
• Water dehydration test, raising Posmolality
to >292 was performed.
• Urine osmolality remained at 50 mosm/kg.
• DI diagnosis established.

- Is it central or nephrogenic?
 Clinical Scenario II
• If a dose of vasopressin was given and
urine osm remained low the diagnosis is…
• If a dose of vasopressin is given and the
Uosm rose to 600 mosm/kg the dx is…

- What would ADH level be if central vs

nephrogenic?
 Clinical Scenario II
• If a dose of vasopressin was given and
urine osm remained low the diagnosis is
Nephrogenic DI.
• If a dose of vasopressin is given and the
Uosm rose to 600 mosm/kg the dx is
Central DI.
• ADH level low if central vs high if
nephrogenic.
 Important Concepts
• The purpose of water homeostasis/osmoregulation is to
prevent osmotically driven changes in CELL VOLUME.
• Cells adapt to chronic changes in plasma [Na]. Keep this in
mind during the treatment of dysnatremias.
– “If it happened fast, correct it fast, if it happened slowly
correct it slowly.”
• Water homeostasis is achieved by regulating ADH and thirst.
• Under normal conditions plasma [Na] is kept constant
predominantly by renal regulation of H2O excretion via ADH.
• With more severe rise in osmolality, the thirst mechanism
becomes activated.
• By and large H2O (ADH/Thirst) and Na balance (Ang-II/ANP)
are independently regulated, BUT the mechanisms are
interconnected.