Plasma osmolality is regulated principally via vasopressin (also
termed anti-diuretic hormone, ADH) release from the posterior pituitary,
or neurohypophysis, whereas volume homeostasis is determined largely through
the action of the renin-angiotensin-aldosterone system, with contributions
from both vasopressin and the natriuretic peptide family. The nine
amino acid peptide vasopressin is synthesized in hypothalamic paraventricular
and supraoptic magnocellular neurons, whose axons travel caudally
and converge at the infundibulum before terminating in the posterior
pituitary, transporting the hormone to its primary site of storage
and release into the systemic circulation (see Fig.
Water balance is regulated in two ways: vasopressin secretion
stimulates water reabsorption by the kidney, thereby reducing future
water losses; and thirst stimulates water ingestion, which restores
past water losses. The two systems work in parallel to efficiently
regulate extracellular fluid tonicity (Fig. 525-1).
However, when both vasopressin secretion and thirst are compromised,
life-threatening abnormalities in plasma osmolality can occur.
Regulation of vasopressin secretion and serum osmolality.
Hyperosmolality, hypovolemia, or hypotension is sensed by osmosensors,
volume sensors, or barosensors, respectively. These stimulate both
vasopressin (VP) secretion and thirst. VP, acting on the kidney,
causes increased reabsorption of water (antidiuresis). Thirst causes
increased water ingestion. The results of these dual negative feedback
loops cause a reduction in hyperosmolality or hypotension/hypovolemia.
Normal blood osmolality ranges between 280 and 290 milliosmoles/kg
H2O (mosm/kg). An osmosensor located outside the
blood-brain barrier near the anterior hypothalamus can detect as
little as 1% to 2% change in blood osmolality.
When osmolality increases above a threshold of 283 mosm/kg,
it signals the posterior pituitary to secrete vasopressin. Hypothalamic
neurons distinct from those that control vasopressin secretion stimulate
thirst sensation at a threshold (~293 mosm/kg) slightly
higher than that for vasopressin release.
Vasopressin is also secreted in response to a decrease in intravascular
volume or pressure. Vasopressin concentration rises exponentially
after a reduction in intravascular volume that exceeds 8%.
When blood volume or blood pressure decreases by 25%, vasopressin
levels rise to 20- to 30-fold above normal, high enough to cause
vasoconstriction and vastly exceeding those required for maximal
antidiuresis (~5 pg/mL). Nausea, pain, hypoglycemia, psychologic stress,
ethanol, and chlorpropamide are also clinically important triggers
for vasopressin release. Vasopressin secretion is inhibited by glucocorticoids.
Once in the circulation, vasopressin has a half-life of only
5 to 10 minutes, due to its rapid degradation by vasopressinase.
The synthetic analog of vasopressin, dDAVP (desmopressin acetate),
is insensitive to this amino-terminal degradation, and thus has
a much longer half-life of 8 to 24 hours.
Vasopressin affects the function of several tissue types by binding
to three G-protein–coupled cell surface receptors, designated
V1, V2, and V3 (or V1b). The V1 receptors on vascular smooth muscle
and hepatocytes mediate vasoconstriction and glycogenolysis, respectively.
The V3 receptors, on corticotrophs in the anterior pituitary, mediate
adrenocorticotrophic hormone (ACTH) secretion. Modulation of water
balance occurs through the action of vasopressin on V2 receptors
located primarily on the basolateral (blood) side of cells in the
renal collecting tubule, where it induces the insertion of aggregates
of the water channel aquaporin-2 into the apical (luminal) membrane.
This allows water movement from the tubular lumen along its osmotic
gradient into the hypertonic inner medullary interstitium and the excretion
of concentrated urine (Fig. 525-2).
Vasopressin (VP) action in the kidney.  VP
binds to the V2 receptor (V2R), causing  dissociation
of the trimeric G protein (α, β, γ)
Gs, allowing Gsα to  activate
adenylate cyclase (AC), resulting in an increase in cyclic adenosine
monophosphate (cAMP) and  activation of protein
kinase A (PKA). The catalytic subunit of PKA phosphorylates the aquaporin-2
(AQP2) water channel, causing it to  aggregate
as a homotetramer in the collecting duct luminal membrane, resulting
in [6 and 7] an increase in water flow down its
osmotic gradient from the urine into the hypertonic renal medullary
interstitium containing NaCl and urea. Demeclocycline, lithium,
high calcium, and low potassium interfere with these processes.
Polyuria, Polydipsia, and Hypernatremia
In children, one must first determine if pathologic polyuria
or polydipsia (> 2 L/m2/d*)
is present, by asking the following questions: (1) Can either polyuria
or polydipsia be quantitated? (2) Have either interfered with normal
activities and do they occur even at night? (3) Do the history,
growth data or physical examination suggest another endocrinopathy
or an intracranial neoplasm? (4) Is there a psychosocial reason
for either polyuria or polydipsia?
If pathologic polyuria or polydipsia is present, the following
laboratory tests should be obtained: serum osmolality, sodium, potassium, glucose,
calcium, and blood urea nitrogen (BUN); and simultaneous measurement
of urine for urine osmolality, specific gravity, glucose concentration,
and urinalysis. A serum osmolality > 300 mosm/kg, with
urine osmolality < 300 mosm/kg, establishes the diagnosis
of diabetes insipidus (DI). If serum osmolality is < 270 mosm/kg,
or urine osmolality is > 600 mosm/kg, the diagnosis of
DI is unlikely. If the serum osmolality is < 300 mosm/kg,
but if there is significant polyuria and polydipsia that cannot
be attributed to primary polydipsia (ie, the serum osmolality >
270 mosm/kg), the patient should undergo a water deprivation
test to establish a diagnosis of DI and to differentiate central
from nephrogenic causes.
After a maximally tolerated overnight fast, the child is deprived
of water at an outpatient testing center under close observation
by personnel experienced with this procedure. Physical signs (weight,
pulse, blood pressure) and laboratory data (serum sodium, osmolality,
hematocrit, urine volume, osmolality, specific gravity) are monitored
during the test. If at any time during the test, the urine osmolality
exceeds 1000 mosm/kg or 600 mosm/kg that is stable
over 1 hour, the patient does not have DI. If at any time the serum
osmolality exceeds 300 mosm/kg and the urine osmolality
is < 600 mosm/kg, the patient has DI. If the serum osmolality
is < 300 mosm/kg and the urine osmolality is < 600 mosm/kg,
the test should be continued unless vital signs disclose hypovolemia.
A common error is to stop a test too soon (especially in patients with
primary polydipsia who are volume overloaded), based on the amount
of body weight lost. If the diagnosis of DI is made, aqueous vasopressin
(Pitressin), 1 mU/m2, should be given subcutaneously.
If the urine volume falls and the osmolality doubles during the
next hour, the patient has central diabetes insipidus (CDI). If
not, the patient probably has nephrogenic diabetes insipidus (NDI).
dDAVP (desmopressin acetate) should not be used for this test because
it has been associated with water intoxication in small children
in this setting.
Magnetic resonance imaging (MRI) is not very helpful in distinguishing
CDI from NDI. Normally, the posterior pituitary is seen as an area
of enhanced brightness in T1-weighted images following administration
of gadolinium. The posterior pituitary “bright spot” is
diminished or absent in both forms of DI, normal in primary polydipsia,
and decreased in syndrome of inappropriate antidiuretic hormone
surface area of the average neonate is ~0.3 m2, average
10-year-old child ~1 m2, and average adult ~1.7 m2