Pediatric Diabetes Insipidus

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). ^{[3, 6]} Eight mutations on AQP2 gene are associated with autosomal dominant NDI, and 32 mutations are associated with autosomal recessive nephrogenic DI. ^[7] The X-linked variety of nephrogenic DI 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. ^[8]

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. ^[9]

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. ^{[10, 11]}

Nongenetic causes

Nongenetic causes of DI include injuries, 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 DI. Central diabetes insipidus is considered idiopathic in 20-50% of cases. ^[2]  However, 2 studies have found a higher prevalence of CNS malformations in patients with CDI than previously reported, as well as fewer idiopathic cases. ^{[12, 13]}  Werny and colleagues reported that children diagnosed with idiopathic CDI with findings of stalk thickening on the initial MRI were more likely to have an underlying diagnosis (40% vs 0%; P = .03). In the study, of 147 patients with CDI (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 CDI was the diagnosis in 12.2% of cases. ^[13]

Genetic causes

Central DI with an autosomal dominant pattern inheritance is due to a mutation in the prepro-arginine 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. ^{[3, 4, 5]} In cases of autosomal recessive or dominant transmission, NDI 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.

DI is a rare disease, with an overall prevalence of 1:25,000. Tumors, infiltrative lesions, malformations, and neurosurgical procedures are the most common causes of DI. Less than 10% of DI is hereditary. X-linked NDI accounts for 90% of cases of congenital NDI and occurs with a frequency of 4 to 8 cases per 1 million male births. Autosomal NDI 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%). ^[2]  

In a large Danish study in 2014, the annual incidence of CDI overall was 3 to 4 patients per 100,000, with an incidence of 2 cases of congenital CDI per 100,000 infants. ^[14]

Age-related demographics

DI occurs across a wide age range. Idiopathic CDI onset can occur at any age but is most often seen in 10- to 20-year-olds. ^[1]  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.

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. However, central DI in the acute phase after traumatic brain injury is associated with hypernatremia and increased intracranial pressure and high mortality rates of 33-82%. ^[15]

The earlier onset of nephrogenic DI 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.

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.)