NEPHROGENIC
DIABETES INSIPIDUS
PATHOPHYSIOLOGY
A detailed description of ADH
physiology is available on Plate 3-17. In brief, elevations in serum osmolality
trigger release of ADH from the posterior pituitary. In the kidneys, ADH binds
to V2 receptors on the basolateral surface of principal cells, located in the
collecting duct, which triggers translocation of aquaporin 2
(AQP-2) channels from endosomes to apical cell membranes. As a result, water is
reabsorbed through a transcellular route from the tubule lumen into the
interstitium. In addition, ADH up-regulates apical ENaC and urea transporters
in the collecting duct, as well as Na+/K+/2Cl- cotransporters (NKCC2) in the thick ascending
limb, to increase the concentration of solute in the interstitium and draw more
water out of the collecting duct.
Inherited NDI, which is the major
cause of NDI in children, typically results from mutations in either the V2
receptor or AQP-2 channel. V2 mutations account for 90% of cases and are
inherited in an X-linked recessive pattern. Females may exhibit a variable
level of disease depending on their particular pattern of X-inactivation
(lyonization). AQP-2 mutations account for most of the remaining cases and can
be inherited in an autosomal recessive or dominant pattern. Other tubular
disorders, such as Bartter syndrome, can also feature increased urine
production because of failure to establish an adequate concentration of solutes
in the medullary interstitium; thus, even though ADH is present and functional,
there is a diminished transcellular gradient for water transport.
Acquired NDI, which is more common
in adults, is most frequently the result of long-term lithium usage, commonly
employed to treat bipolar disorder. About 40% to 50% of patients who take
lithium will experience this complication to some degree; among them, about
half will experience significant polyuria, starting as early as 8 weeks after
therapy begins. Lithium is freely filtered at the glomerulus and primarily reabsorbed
in the proximal tubule. A small amount, however, is reabsorbed through apical
ENaC in principle cells of the collecting duct. It accumulates within the cell,
where it appears to interfere with the second messenger cascade that connects
V2 activation to luminal insertion of AQP-2 channels. For reasons that are
poorly under-stood, but which may involve a selective toxic effect on principal
cells, these effects can persist even after lithium is discontinued.
Other drugs that may cause diabetes
insipidus include demeclocycline, amphotericin B, and orlistat. The mechanisms
are diverse and not completely under-stood. V2 receptor antagonists, such as
tolvaptan, may cause transient NDI. Finally, acquired NDI may also occur in the
setting of normal aging, which causes a decreased density of collecting duct
transporters; hypercalcemia and hypokalemia because these states interfere with
reabsorption in the thick ascending limb and therefore decrease the medullary
solute gradient; release of bilateral ureteral obstructions
because of tubular injury; and amyloidosis, if there is extensive tubular
deposition.
PRESENTATION AND DIAGNOSIS
The major symptom of both central
and nephrogenic DI is polyuria, arbitrarily defined as greater than 3 L/ day of
urine production in adults and 2 L/day in children. Additional features often
include constant thirst (polydipsia)
and fatigue. In children with inherited NDI, failure to thrive and mental
retardation may occur secondary to repeated episodes of severe dehydration, if
diagnosis and treatment have been delayed. Patients with polyuria should be
questioned regarding their water intake to assess for possible primary
polydipsia (i.e., compulsive water consumption, which leads by necessity to
polyuria). In addition, their medications should be carefully reviewed to
determine if they are taking diuretics or medications (such as lithium) known
to cause DI. A prior history of trans-sphenoidal neurologic surgery strongly
suggests central DI. Finally, family history should be assessed for possible
inherited disease.
On serum chemistries, hypernatremia
is suggestive of severe dehydration secondary to polyuria, whereas hyponatremia
indicates primary polydipsia. Hypokalemia and hypercalcemia may cause NDI, as
previously stated, and should be noted if present. Fasting glucose levels
should be normal to exclude hyperglycemia as a cause of osmotic diuresis. Serum
creatinine concentration may be slightly elevated in the setting of severe
dehydration, with an elevated BUN:creatinine ratio and bland urine sediment
suggestive of a prerenal state (see Plate 4-1).
In children and adults, a water
deprivation test is the gold standard for diagnosis. This procedure tests the
urine-concentrating capabilities of the kidneys in response to dehydration. In
normal individuals, there will be an appropriate increase in urine osmolality
as the body attempts to conserve free water. In patients with DI, in contrast,
the urine osmolality remains depressed, with the exact level depending on
various testing parameters and whether the DI is complete or partial. The
distinction between central and nephrogenic DI may be established by assessing
the response to exogenous vasopressin agonists, such as desmopressin, which
will lead to urine concentration in central DI but have no effect in
nephrogenic DI.
Of note, patients with primary
polydipsia may have findings that resemble those of partial NDI because their
urine-concentrating abilities are frequently impaired (as a result of medullary
wash-out) but the addition of desmopressin has no effect (since they have
intact secretion of endogenous ADH). Thus a careful history
may be required to make the distinction.
TREATMENT
All potentially modifiable causes of
NDI should be reversed. Lithium, for example, should be discontinued, and
hypokalemia or hypercalcemia should be corrected. These measures may lead to
complete recovery of renal function, although lithi m-associated NDI may be
irreversible in some cases.
It is important for all patients to
maintain adequate hydration. If young children cannot obtain their own water,
it must regularly be offered to them. A low-salt diet should be instituted to
promote solute and water reabsorption in the proximal tubule.
In addition, a diuretic can be
offered because it can paradoxically reduce urine output by causing a slight
volume depletion, which up-regulates salt and water reabsorption
in the proximal tubule. Thiazide diuretics are preferred over loop diuretics
because the latter impair creation of the solute gradient in the medulla, which
interferes with urine concentration. In addition, amiloride has been proposed
as a potentially preventative measure in patients taking lithium, because this
agent appears to limit lithium influx into principal cells. Its
efficacy, however, remains unknown.
