Pediatric Diabetes Insipidus

Author: James CM Chan, MD; Chief Editor: Stephen Kemp, MD, PhD

Background
Diabetes is a Greek word meaning siphon; it is derived from the verb diabainein, which means
to stand with legs apart (as in urination) or to go through. Insipidus is a Latin word meaning
without taste. In contrast to diabetes mellitus, which involves the excretion of sweet urine,
diabetes insipidus (DI) involves the passing of urine that is tasteless because of its relatively low
sodium content.
DI is due either to (1) deficient secretion of arginine vasopressin (AVP)also known as
antidiuretic hormone (ADH)by the pituitary gland (central or neurogenic DI) or to (2) renal
tubular unresponsiveness to ADH (nephrogenic DI).
For central (neurogenic) DI, the treatment of choice is the synthetic ADH analogue desmopressin
(1-deamino-8-D-arginine vasopressin [DDAVP]). Other useful medications include
chlorpropamide and thiazide diuretics. Nephrogenic DI cannot be effectively treated with
desmopressin, because the receptor sites are defective and the kidney is prevented from
responding. Thiazide diuretics, amiloride, and indomethacin or aspirin are useful when coupled
with a low-solute diet.

Pathophysiology
The basis of water loss in DI is distinct from that of water loss caused by diabetes mellitus. The
renal tubular collecting ducts are unable to concentrate urine secondary to ADH deficiency or
resistance.
The collecting duct concentrates urine by reabsorbing water, a function controlled by the
posterior pituitary gland via secretion of AVP (ie, ADH). Reabsorption of sugars, amino acids,
and virtually all electrolytes is completed by the time the urine has reached this segment of the
nephron. Thus, the inability to conserve water by reabsorption in the collecting duct depletes
body water but leaves sodium unaffected. The net result is an extremely diluted, increased urine
output resulting in hypernatremia. Polydipsia follows, as the thirst mechanism urges
replenishment of body water.
Secretion of ADH occurs in the posterior pituitary gland and is regulated at the paraventricular
and supraoptic nuclei, which sense changes in osmolality. Destruction of the paraventricular or
supraoptic nuclei or of the posterior pituitary by tumor, pressure, or surgical ablation results in
decreased ADH secretion and central DI. Alternatively, DI may be idiopathic or inherited as
either an autosomal dominant or an autosomal recessive trait (locus 20p13).

Nephrogenic DI arises from defective or absent receptor sites at the cortical collecting duct
segment of the nephron (X-linked, vasopressin V2 receptor deficiency, locus Xq28) or defective
or absent aquaporin, the protein that transports water at the collecting duct (autosomal recessive,
locus 12q13).[1, 2] Eight mutations on AQP2 gene are associated with autosomal dominant
nephrogenic DI, and 32 mutations are associated with autosomal recessive nephrogenic DI.[3] The
X-linked variety of nephrogenic DI accounts for about 90% of all such cases.
As a consequence of one of these defects, the ducts do not appropriately respond to ADH.
Normally, ADH is transported in the blood to receptor sites on the basolateral surface of the
collecting duct membrane. Through a G proteinadenylate cyclase coupling, activation of the
ADH receptor increases cyclic adenosine monophosphate (cAMP) production and stimulates
protein kinase A, leading to increased recycling of the protein aquaporin in the plasma
membrane.
In the presence of ADH stimulus, exocytic insertion of aquaporin into the apical, or luminal,
surface of the tubule cell occurs. Aquaporin enhances water entry into the cell from the lumen.
Absence of the ADH receptor does not allow this process to take place, causing inhibition of
water uptake and polyuria. Alternatively, defective or absent aquaporin impairs the process in the
presence of normal V2 receptors.

Etiology
DI is due either to (1) deficient secretion of ADH by the pituitary gland (central or neurogenic
DI) or to (2) renal tubular unresponsiveness to vasopressin (nephrogenic DI). Both genetic and
nongenetic causes are known.[4, 5]
Nongenetic causes

Nongenetic causes of DI include injuries. Typical injuries include head trauma, tumor, and
neurosurgical procedures. At all ages, destructive lesions of the pituitary, the hypothalamus, or
both are the most common cause of DI.
Genetic causes

Central DI with an autosomal dominant pattern inheritance is due to a mutation in the preproarginine vasopressin (prepro-AVP2) gene, mapped to locus 20p13. Central DI with diabetes
mellitus, optic atrophy, and mental retardation (Wolfram syndrome) may be inherited in an
autosomal recessive pattern (locus 4p16) or may be due to mitochondrial deletions.
X-linked nephrogenic DI occurs from mutations in the antidiuretic arginine vasopressin V2
receptor (AVPR2) gene, mapped to Xq28.[1, 6, 7] Nephrogenic DI with an autosomal dominant or
recessive pattern is due to mutations in the gene designated AQP2; this gene directs water
channel formation in the distal membrane and has not yet been mapped.

Epidemiology
United States statistics

Tumors, infiltrative lesions, malformations, and neurosurgical procedures are the most common
causes of central DI. Of the genetic etiologies, the overall incidence in the general population is
estimated to be 3 cases per 100,000 population (0.003%). The male-to-female ratio is 60:40. Xlinked nephrogenic DI is very rare, although it exceeds the recessive variety in frequency by a
ratio of 9:1. The rate of mutation for males is 4 cases per million population.
Age-related demographics

DI occurs across a wide age range. Children who present with autosomal recessive central DI are
generally younger than 1 year; those who present with autosomal dominant central DI are often
older than 1 year. Nephrogenic DI (including X-linked, autosomal dominant, and autosomal
recessive forms) develops in early infancy, often in neonates younger than 1 week.
Sex-related demographics

Central DI secondary to hypothalamic-pituitary lesions occurs at random and should, therefore,

be evenly distributed between the sexes. Autosomal dominant and autosomal recessive central DI
occur equally in both sexes. Nephrogenic DI caused by an X-linked mutation affects only males.
Autosomal dominant and autosomal recessive forms of nephrogenic DI equally affect both sexes.

Prognosis
Long-term survival in cases of central DI depends on the precipitating cause. In primary central
DI, the prognosis is excellent with early recognition and appropriate desmopressin therapy.
The earlier onset of nephrogenic DI and the reduced ability to treat this variety of the disease
renders the child more prone to attention deficit, hyperactivity, learning disorders, and
psychomotor delay.
As long as water remains available at all times to replace the massive losses, long-term survival
is not in question.

Patient Education
Parents must be educated regarding water replacement in infants and young children who cannot
express thirst or access fluids without assistance. Gastrointestinal illnesses that cause decreased
intake, increased stool losses, or both must receive early and serious attention to prevent lifethreatening electrolyte and fluid balance abnormalities. (See the videos below.)
Diabetes Sick Day Rules.
Taking Diabetes Back to School.
Proceed to Clinical Presentation

History
Diagnosis of diabetes insipidus (DI) may be difficult in infants and children because of
nonspecific presenting features (eg, poor feeding, failure to thrive, irritability). Accordingly, a
high index of suspicion is necessary.
The earliest signs of DI include a vigorous suck with vomiting, fever without apparent cause,
constipation, and excessively wet diapers from urination. In older infants and young children,
irritability is generally due to a borderline state of dehydration coupled with hypernatremia and,
sometimes, fever. Nocturia is common and expected because of increased urine production.
Central DI tends to develop suddenly.

Physical Examination
The typical examination reveals an irritable infant with a dripping wet diaper, along with
detectable signs of dehydration (eg, dry mucous membranes, diminished skin turgor, decreased
tearing, tachycardia). Often, skin turgor is not diminished in individuals with hypernatremic
dehydration despite significant dehydration. In severely dehydrated patients, the pulse may be
thready and rapid. Hypotension may be present because of hypovolemic shock. Mobile fecaliths
may be palpable in the abdomen.

Complications
Complications include the following:

Growth failure

Nocturia and enuresis

Hypernatremic dehydration

Seizures

Mental retardation

Dehydration results from an inability to reabsorb free water at a site distal to electrolyte
reabsorption. Any patient unable to continuously replace water loss is vulnerable to dehydration,
especially in warm weather when insensible water loss through perspiration and respiration
substantially increases risk.
Electrolyte abnormalities are caused by the loss of urinary free water, which produces
hyperosmolar dehydration, leading to hypernatremia, hyperchloremia, and prerenal azotemia.
Diminished blood volume increases blood viscosity and the risk of sludging and thrombosis.

Failure to thrive occurs because of the patients constant thirst conferring a sense of fullness that
offsets the sense of hunger. The affected individual eats less than necessary for normal growth.
Seizures are a consequence of the electrolyte abnormalities introduced in the central nervous
system (CNS) by severe hypernatremia and hyperosmolar dehydration. Mental retardation results
from the damage to the CNS caused by severe hyperosmolarity, seizures, and potential hypoxia,
all of which are thought to account for the frequent occurrence of mental retardation. Death can
occur from a hypovolemic shock or a hypernatremic seizure.
Proceed to Differential Diagnoses

Differential Diagnoses

Diabetes Mellitus, Type 1

Head Trauma

Histiocytosis

Hypercalcemia

Hypokalemia

Medullary Cystic Disease

Sickle Cell Anemia

Type 1 Diabetes Mellitus

Proceed to Workup

Basic Laboratory Studies

In assessing patients with suspected diabetes insipidus (DI), the urine specific gravity of the first
morning urine is helpful in assessing renal ability to concentrate urine. Dilute urine with a
relatively high serum sodium and osmolarity effectively establishes the diagnosis. The serum
sodium level may be as high as 170 mEq/L, while the serum osmolarity is greater than 300
mOsm/kg. Patients with prerenal azotemia present with severe dehydration.
In young infants, distinguishing between normal and pathologic inability to concentrate the urine
may be difficult because infants generally exhibit a constitutional hyposthenuria.

An accurate 24-hour urine collection is important. The total urine output is high, and the number
of osmoles excreted per day is small.
Serum potassium and calcium concentrations are important to exclude the possibility of polyuria
secondary to hypokalemia or hypercalcemia, both of which interfere with renal concentrating
mechanisms.

Water Deprivation Testing

The definitive diagnostic study is the water deprivation test, which can be used both to confirm
the diagnosis and to distinguish between central DI and nephrogenic DI on the basis of response
to a vasopressin analogue.
The water deprivation test is performed as follows:

Obtain baseline urine and blood for osmolality and electrolytes.

Deprive the patient of water after breakfast until significant dehydration

occurs. Weigh the patient every 2 hours and limit dehydration to 2-5% loss of
body weight.

Monitor urine specific gravity hourly; if the specific gravity is 1.014 or greater,
terminate the test and obtain appropriate urine and blood specimens for
osmolality. Limit water deprivation to 4 hours for infants and 7 hours for
children.

If polyuria persists, administer intranasal desmopressin (see Medication), and

replace urine output with fluids. After 4 hours (2 h in infants), obtain urine
and blood for osmolality.

The normal response to dehydration or desmopressin includes urine osmolality greater than 450
mOsm/kg, a urine-to-serum osmolality ratio of 1.5 or higher, and an increase in urine-to-serum
osmolality of 1.0 or more from baseline. A normal response should be observed in central DI and
psychogenic DI but not in nephrogenic DI.

Magnetic Resonance Imaging

Cranial magnetic resonance imaging (MRI) can be used to exclude pituitary cysts, hypoplasia,
and destruction secondary to mass lesions.[8] Often, the bright spot on an MRI scan that is thought
to represent vasopressin-secreting neurons in the posterior pituitary is absent in patients with
central DI.
Proceed to Treatment & Management

Approach Considerations
Treat patients with diabetes insipidus (DI) in an inpatient setting because of the risk of severe
dehydration. Destructive or compressive intracranial lesions mandate inpatient stay.
Demonstration of an intracranial mass necessitates surgical care.
Distinguishing between central and nephrogenic etiologies is essential to treatment.[9] Transfer to
an academic center is highly advised for initial diagnosis and treatment, especially because
central DI may require involved diagnostic studies and neurosurgical or oncologic treatment.
Surgical procedures of any kind require replacement of fluids at a much higher rate than normal
maintenance; inattention to this may result in serious consequences.
Subsequent admissions are determined by the need for intravenous (IV) rehydration, especially
during intercurrent gastrointestinal (GI) illnesses.

Pharmacologic Therapy
For central DI, the treatment of choice is desmopressin (a synthetic vasopressin analogue). It is
available in parenteral, intranasal, and oral dosage forms. The doses widely vary depending on
the preparation used, so take care to correctly calculate the dose. Other useful medications
include chlorpropamide and thiazide diuretics. The latter 2 can result in a 25-75% reduction in
urine volume and can be used in combination with each other.
Nephrogenic DI cannot be effectively treated with desmopressin, because the receptor sites are
defective and the kidney is prevented from responding. Thiazide diuretics, amiloride,[10, 11] and
indomethacin or aspirin are useful when coupled with a low-solute diet.
Aqueous vasopressin (Pitressin) and desmopressin (DDAVP) preparations are available for
intravenous (IV) use in emergency circumstances. Overtreatment with desmopressin can result in
hyponatremia and seizures.

Diet and Activity

Provide affected infants with a breast milk diet to decrease solute load. Protein should account
for 6% of caloric intake, and sodium should be reduced to 0.7 mEq/kg/day.
Provide young children with 8% of their caloric intake in the form of protein to enable normal
growth. Sodium intake must be maintained at 0.7 mEq/kg/day. (See the video below.)
Carbs for Kids-Count Them In: The Constant Carbohydrates Diet.

Activities resulting in increased insensible water loss should be moderated in the presence of
massive urinary water loss to prevent dehydration. Heat exposure should be minimized,
especially when participating in sports. Avoid creating barriers to drinking water.

Consultations and Long-Term Monitoring

Consultation with the following specialists may be appropriate:

Nephrologist

Endocrinologist - The presence of central DI should prompt an evaluation of

anterior pituitary function.

Diagnostic radiologist

Regular follow-up visits with an endocrinologist (for central DI) or a nephrologist (for
nephrogenic DI) are necessary for dosage adjustment. When indomethacin is used in long-term
therapy, carefully observe renal function for any signs of toxicity.
Proceed to Medication

Medication Summary
For central diabetes insipidus (DI), the treatment of choice is desmopressin (a synthetic
antidiuretic hormone [ADH] analogue). It is available in parenteral, intranasal, and oral dosage
forms. The doses widely vary depending on the preparation used, so take care to correctly
calculate the dose. Other useful medications include chlorpropamide and thiazide diuretics. The
latter 2 can result in a 25-75% reduction in urine volume and can be used in combination with
each other.
Nephrogenic DI cannot be effectively treated with desmopressin, because the receptor sites are
defective and the kidney is prevented from responding. Thiazide diuretics, amiloride, and
indomethacin or aspirin are useful when coupled with a low-solute diet.

Pituitary Hormones
Class Summary

DI of central origin is due to absence of vasopressin secretion by the pituitary. Consequently, use
of a synthetic vasopressin analogue (ie, desmopressin) is required. The natural compound
vasopressin (ie, antidiuretic hormone [ADH]) may be used to diagnose nephrogenic DI. It has a
very short natural half-life. This permits its safe use in distinguishing central DI from
nephrogenic DI by obviating prolonged fluid accumulation in the former. As an aqueous
preparation, it can be administered parenterally, intramuscularly (IM), or subcutaneously.
View full drug information
Desmopressin acetate (DDAVP)

Desmopressin is a synthetic analogue (1-[3-mercaptopropionic acid]-8-D-arginine vasopressin

monoacetate trihydrate) of pituitary ADH. It increases the cellular permeability of collecting
ducts, resulting in reabsorption of water by kidneys.
Dosage must be individualized. The drug is supplied as parenteral (4 g/mL), nasal (100 g/mL
rhinal tube), and oral (0.1- and 0.2-mg tab) preparations.
View full drug information
Vasopressin (Pitressin)

Vasopressin has vasopressor and ADH activity. It increases water resorption at the distal renal
tubular epithelium (ADH effect) and promotes smooth muscle contraction throughout the
vascular bed of the renal tubular epithelium (vasopressor effects). However, vasoconstriction is
also increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic
vessels.
Use only the aqueous preparation, which has a short half-life. Vasopressin tannate in oil, which
has a longer action, should not be used.

Anticonvulsants
Class Summary

Certain antiepileptic drugs, such as carbamazepine, have proven helpful in DI.

View full drug information
Carbamazepine (Tegretol, Carbatrol, Equetro)

Carbamazepine ameliorates DI by releasing ADH. It is not useful in total DI and generally is not
a first-line drug.

Diuretic Agents
Class Summary

Thiazide diuretics impair sodium chloride reabsorption in the distal tubule, reducing the loss of
free water to the collecting system and increasing urine concentration. The reduction in urine
volume derives from a concomitant action on the proximal tubule, which causes enhanced
reabsorption of isoosmotic sodium chloride from the glomerular filtrate, thus drawing additional
water along. The net result of both processes is a smaller volume and a higher concentration of
the urine.

View full drug information

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide is a thiazide diuretic. The combination of decreased free water delivery to

distal tubule and increased sodium chloride reabsorption in proximal tubule underlies its efficacy
in DI therapy.
View full drug information
Amiloride (Midamor)

Amiloride is a potassium-sparing diuretic. It has a potassium-sparing effect, so the risk of

hypokalemia is decreased in combination with hydrochlorothiazide. In addition, the 2 agents are
synergistic with respect to antidiuresis.

Nonsteroidal Anti-inflammatory Drugs

Class Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) act synergistically with thiazides to diminish

urine volume, although the precise mechanism is unknown.
View full drug information
Ibuprofen (Caldolor, Advil, Motrin)

Inhibition of prostaglandin synthesis reduces the delivery of solute to distal tubules, reducing
urine volume and increasing urine osmolality. Ibuprofen is usually used in nephrogenic DI.
View full drug information
Indomethacin (Indocin)

Indomethacin is a nonsteroidal prostaglandin inhibitor with antipyretic properties.

Sulfonylurea Compounds
Class Summary

Sulfonylurea compounds are an alternative therapy to desmopressin and can be used in

combination with thiazide diuretics. Sulfonylurea compounds have the reported property of
causing a syndrome identical to inappropriate ADH secretion.

View full drug information

Chlorpropamide

Chlorpropamide promotes renal response to ADH. In central DI, ADH secretion is absent,
although ADH receptor sites remain present in the kidney. Thus, interaction of the receptors with
sulfonylurea compounds can produce a physiologic antidiuresis.
Dosage must be individualized. The agent is available only in tab form.