Pediatric Arginine Vasopressin Disorders (Diabetes Insipidus)

Arginine vasopressin (AVP) deficiency (AVP-D) and AVP resistance (AVP-R) (formerly known as central or neurogenic diabetes insipidus and nephrogenic diabetes insipidus, respectively[1, 2] ) are part of a group of hereditary or acquired polyuria and polydipsia diseases in which the kidneys pass large amounts of water irrespective of the body's hydration state. AVP disorders are due either to (1) deficient secretion of antidiuretic hormone (ADH) by the pituitary gland (AVP-D) or to (2) renal tubular unresponsiveness to vasopressin (AVP-R).

The hallmarks of AVP-D are polyuria (urine volume in excess of 150 ml/kg/24 hr at birth, 100-110 ml/kg/24 hr until the age of 2 years, and 40-50 ml/kg/24 hr in older children and adults), dilute urine (osmolality < 300 mOsm/L), and polydipsia (water intake of up to 20 L/day).[3] AVP-R is characterized by polyuria with polydipsia, recurrent bouts of fever, constipation, and acute hypernatremic dehydration after birth that may cause neurologic sequelae.

Acquired AVP-D can occur at any age and is usually secondary to a condition damaging the central nervous system. Typical injuries include head trauma, tumor, and neurosurgical procedures. AVP-D is considered idiopathic in 20-50% of cases.[4]

AVP-D with an autosomal dominant pattern inheritance is due to a mutation in the prepro-arginine vasopressin (prepro-AVP2) gene, mapped to locus 20p13. AVP-D with diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome) may be inherited in an autosomal recessive pattern (locus 4p16) or may be due to mitochondrial deletions.[2, 3, 5]

In up to 90% of cases, AVP-R is caused by mutations in the gene located on Xq28 coding for the V2 receptor of antidiuretic hormone (AVPR2).[6, 7, 8, 9] In cases of autosomal recessive or dominant transmission, AVP-R is caused by mutations in the AQP2 gene (located on chromosome 12) that codes for aquaporin-2. Aquaporin-2 is involved in the transportation of water in the renal tubules.

For AVP-D, 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. AVP-R 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.

The basis of water loss in arginine vasopressin (AVP) disorders (eg, AVP deficiency [central diabetes insipidus], AVP resistance [nephrogenic diabetes insipidus], and syndrome of inappropriate secretion of antidiuretic hormone [SIADH]) 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.[10]

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 AVP deficiency (AVP-D) . Alternatively, diabetes insipidus may be idiopathic or inherited as either an autosomal dominant or an autosomal recessive trait (locus 20p13).

AVP resistance (AVP-R) (nephrogenic diabetes insipidus) 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).[6, 11, 12] Eight mutations on AQP2 gene are associated with autosomal dominant AVP-R, and 32 mutations are associated with autosomal recessive AVP-R.[13] The X-linked variety of AVP-R accounts for about 90% of all such cases. It should be noted that the protein aquaporin-1 is a water channel expressed in the proximal tubule and in the thin descending limb of the loop of Henle and is not regulated by vasopressin. Although individuals with deficient aquaporin-1 have been shown to have impaired concentrating ability, under normal conditions such individuals are clinically unaffected.[14]

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 protein–adenylate 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. The subject of osmotic regulation has been reviewed by Danziger and Zeidel.[15]

Arginine vasopressin (AVP) disorder (diabetes insipidus) is due either to (1) deficient secretion of ADH by the pituitary gland (arginine vasopressin deficiency [AVP-D]) (central diabetes insipidus) or to (2) renal tubular unresponsiveness to vasopressin (AVP resistance [AVP-R]) (nephrogenic diabetes insipidus). Both genetic and nongenetic causes are known.[16, 17]

Nongenetic causes

Nongenetic causes of AVP disorder include injuries and illness, with typical ones including head trauma, tumor, and neurosurgical procedures. At all ages, destructive lesions of the pituitary, the hypothalamus, or both are the most common cause of AVP disorder. AVP-D is considered idiopathic in 20-50% of cases.[4] However, two studies have found a higher prevalence of CNS malformations in patients with AVP-D than previously reported, as well as fewer idiopathic cases.[18, 19] Although a causal relationship has not been proven, COVID-19 has been implicated in the pathogenesis of AVP-D.[20]

Werny and colleagues reported that children diagnosed with idiopathic AVP-D with findings of stalk thickening on the initial MRI were more likely to have an underlying diagnosis (40% vs 0%; P = 0.03). In the study, of 147 patients with AVP-D (mean age 7 yr at diagnosis, mean follow-up 6.2 yr), the most common single diagnosis was craniopharyngioma (25.2%), followed by septo-optic dysplasia (14.3%), and Langerhans cell histiocytosis (LCH) (12.2%). Idiopathic AVP-D was the diagnosis in 12.2% of cases.[19]

Genetic causes

AVP-D with an autosomal dominant pattern inheritance is due to a mutation in the prepro-arginine vasopressin (prepro-AVP2) gene, mapped to locus 20p13. AVP-D with diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome) may be inherited in an autosomal recessive pattern (locus 4p16) or may be due to mitochondrial deletions.[2, 3, 5]

X-linked AVP-R occurs from mutations in the antidiuretic arginine vasopressin V2 receptor (AVPR2) gene, mapped to Xq28.[6, 7, 8] In cases of autosomal recessive or dominant transmission, AVP-R is caused by mutations in the AQP2 gene (located on chromosome 12) that codes for aquaporin-2. Aquaporin-2 is involved in the transportation of water in the renal tubules.

Arginine vasopressin (AVP) disorder (diabetes insipidus) is a rare disease, with an overall prevalence of 1:25,000.[21] Tumors, infiltrative lesions, malformations, and neurosurgical procedures are the most common causes of AVP disorders. Less than 10% of AVP disorder is hereditary. X-linked AVP resistance (AVP-R) (nephrogenic diabetes insipidus) accounts for 90% of cases of congenital AVP-R and occurs with a frequency of 4 to 8 cases per 1 million male births. Autosomal AVP-R accounts for approximately 10% of cases. Of the genetic etiologies, the overall incidence in the general population is estimated to be 3 cases per 100,000 population (0.003%).[4]

In a large Danish study in 2014, the annual incidence of AVP deficiency (AVP-D) (central diabetes insipidus) overall was 3 to 4 patients per 100,000, with an incidence of 2 cases of congenital AVP-D per 100,000 infants.[22]

Age-related demographics

AVP disorder occurs across a wide age range. Idiopathic AVP deficiency (AVP-D) onset can occur at any age but is most often seen in 10- to 20-year-olds.[3] Children who present with autosomal recessive AVP-D are generally younger than 1 year; those who present with autosomal dominant AVP-D are often older than 1 year. AVP-R (including X-linked, autosomal dominant, and autosomal recessive forms) develops in early infancy, often in neonates younger than 1 week.

Sex-related demographics

AVP-D secondary to hypothalamic-pituitary lesions occurs at random and should, therefore, be evenly distributed between the sexes. Autosomal dominant and autosomal recessive AVP-D occur equally in both sexes. AVP-R caused by an X-linked mutation affects only males. Autosomal dominant and autosomal recessive forms of AVP-R equally affect both sexes.

Long-term survival in cases of arginine vasopressin deficiency (AVP-D) (central diabetes insipidus) depends on the precipitating cause. In primary AVP-D, the prognosis is excellent with early recognition and appropriate desmopressin therapy. However, AVP-D in the acute phase after traumatic brain injury is associated with hypernatremia and increased intracranial pressure and high mortality rates of 33-82%.[23]

The earlier onset of AVP resistance (AVP-R) (nephrogenic diabetes insipidus) and the reduced ability to treat this variety of the disease render 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.

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 patient’s 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.

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 life-threatening electrolyte and fluid balance abnormalities. (See the videos below.)

Diagnosis of arginine vasopressin (AVP) disorder (diabetes insipidus) 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 AVP disorder 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. AVP deficiency (central diabetes insipidus) tends to develop suddenly.

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.

In assessing patients with suspected arginine vasopressin (AVP) disorder (diabetes insipidus), 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.

Copeptin concentration testing

In a prospective, multicenter, observational cohort study, a single baseline copeptin level greater than 21.4 pmol/L differentiated AVP resistance (AVP-R) (nephrogenic diabetes insipidus) from other etiologies with a 100% sensitivity and specificity and eliminated the need for water deprivation testing.[24] In another study, in patients undergoing pituitary procedures, low copeptin levels were indicative of postoperative AVP deficiency (AVP-D) (central diabetes insipidus), whereas high levels virtually excluded it.[26]

The definitive diagnostic study is the water deprivation test, which can be used both to confirm the diagnosis and to distinguish between arginine vasopressin deficiency (AVP-D) (central diabetes insipidus) and AVP resistance (AVP-R) (nephrogenic diabetes insipidus) 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, and replace urine output with fluids. After 4 hours (2 hr 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 AVP-D and psychogenic polydipsia but not in AVP-R.

Brain magnetic resonance imaging (MRI) at diagnosis can help determine the underlying cause of arginine vasopressin deficiency (AVP-D) (central diabetes insipidus). It can be used to exclude pituitary cysts, hypoplasia, and destruction secondary to mass lesions.[27] Diagnosis is confirmed via absence of the posterior pituitary bright spot (PPBS), which is nearly universal in patients with AVP-D, with the sensitivity of this MRI finding typically reported as between 90% and 100%.[19]

Infants ingest relatively large amounts of low renal solute load fluids, either as breast milk or formula, and have a relatively high-volume of dilute urine output to maintain sodium/water homeostasis. In arginine vasopressin (AVP) disorders (diabetes insipidus), increased fluid turnover is managed by increased free water intake and/or decreased urine output.

Treat patients with an AVP disorder 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.[28] Transfer to an academic center is very strongly advised for initial diagnosis and treatment, especially because AVP deficiency (AVP-D) (central diabetes insipidus) 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 rehydration, especially during intercurrent gastrointestinal illnesses.

Treatment regimens currently in use have recently been reviewed.[29]

For arginine vasopressin deficiency (AVP-D) (central diabetes insipidus), 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 care must be taken to correctly calculate the dose. Other useful medications include chlorpropamide and thiazide diuretics,[30] which can result in a 25-75% reduction in urine volume and can be used in combination with each other.

AVP resistance (AVP-R) (nephrogenic diabetes insipidus) cannot be effectively treated with desmopressin, because the receptor sites are defective and the kidney is prevented from responding. Thiazide diuretics, amiloride,[31, 32] and indomethacin or aspirin are useful when coupled with a low-solute diet. This approach does not normalize urine output and continues to necessitate increased oral fluid intake.

Aqueous vasopressin and desmopressin preparations are available for intravenous use in emergency circumstances. Overtreatment with desmopressin can result in hyponatremia and seizures. Subcutaneous, intranasal, or oral tablet desmopressin therapy is challenging for caregivers to titrate in a dose appropriate for infants. In one study, dilute intranasal desmopressin administered buccally was found to be a safe treatment alternative for AVP-R in infancy.[33] Mavinkurve et al detailed the oral use of diluted nasal desmopressin in treatment of a neonate with AVP-D.[34]

Provide infants with arginine vasopressin (AVP) disorders (diabetes insipidus) 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.)

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.

Consultation with the following specialists may be appropriate:

• Nephrologist

• Endocrinologist: The presence of AVP deficiency (AVP-D) (central diabetes insipidus) should prompt an evaluation of anterior pituitary function

• Diagnostic radiologist

Regular follow-up visits with an endocrinologist (for AVP-D) or a nephrologist (for AVP resistance [AVP-R]) (nephrogenic diabetes insipidus) are necessary for dosage adjustment. When indomethacin is used in long-term therapy, carefully observe renal function for any signs of toxicity.

For arginine vasopressin deficiency (AVP-D) (central diabetes insipidus), the treatment of choice is desmopressin (a synthetic antidiuretic hormone [ADH] analogue). It is available in parenteral, intranasal, and oral dosage forms. The doses vary widely depending on the preparation used, so take care to correctly calculate the dose. Other useful medications include chlorpropamide and thiazide diuretics, which can result in a 25-75% reduction in urine volume and can be used in combination with each other.

AVP resistance (AVP-R) (nephrogenic diabetes insipidus) 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.

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.

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 µg/mL), nasal (100 µg/mL rhinal tube), and oral (0.1- and 0.2-mg tab) preparations.

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.

Class Summary

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

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.

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.

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.

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.

Class Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) act synergistically with thiazides to diminish urine volume, although the precise mechanism is unknown.

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.

Indomethacin (Indocin)

Indomethacin is a nonsteroidal prostaglandin inhibitor with antipyretic properties.

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.

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.