Fluid homeostasis requires adequate water intake, regulated by an intact thirst mechanism and appropriate free water excretion by the kidneys, mediated by appropriate secretion of arginine vasopressin (AVP, also known as antidiuretic hormone). AVP exerts its antidiuretic action by binding to the X chromosome-encoded V2 vasopressin receptor (V2R), a G proteincoupled receptor on the basolateral membrane of renal collecting duct epithelial cells. After V2R activation, increased intracellular cyclic adenosine monophosphate mediates shuttling of the water channel aquaporin 2 to the apical membrane of collecting duct cells, resulting in increased water permeability and antidiuresis. Clinical disorders of water balance are common, and abnormalities in many steps involving AVP secretion and responsiveness have been described. This article focuses on the principal disorders of water balance, diabetes insipidus, and the syndrome of inappropriate antidiuretic hormone secretion.
Pediatric disorders of water balance
Under normal circumstances, plasma osmolality is maintained within a relatively narrow range (280–295 mOsm/kg). This homeostasis requires adequate water intake, regulated by an intact thirst mechanism and appropriate free water excretion by the kidneys, mediated by appropriate secretion of arginine vasopressin (AVP, also known as antidiuretic hormone). AVP is produced by a subset of magnocellular neurons in the paraventricular nuclei (PVN) and supraoptic nuclei (SON) of the hypothalamus. Axons from these neurons project via the pituitary stalk to the posterior pituitary gland. The terminals of these axons contain neurosecretory granules that store AVP for release. A gene on chromosome 20p13 encodes AVP and its carrier protein, neurophysin II (NPII). AVP and NPII are synthesized as a single polypeptide, cleaved within the neurosecretory granules and then reassembled into AVP-NPII complexes before secretion. Stores of preformed AVP in the posterior pituitary can last for 30 to 50 days under basal circumstances or for 5 to 10 days during maximal stimulation. This significant storage capacity explains why a defect in AVP synthesis may not become clinically apparent until weeks after a causal insult, and a partial defect may only be revealed after prolonged water deprivation.
AVP synthesis, transport, and secretion are regulated primarily by changes in plasma osmolality and, to a lesser degree, by changes in circulating volume. Osmoreceptors in the hypothalamus (organum vasculosum of the lamina terminalis and anterior hypothalamus) stimulate secretion of AVP when plasma osmolality increases by as little as 1% in healthy individuals. Basal AVP levels are normally low, 0.5 to 2 pg/mL, and do not increase until plasma osmolality exceeds 280 mOsm/kg. Maximum urine concentration (urine osmolality 900–1200 mOsm/kg) is attained at plasma AVP levels of 5 to 6 pg/mL. Although plasma AVP can continue to rise above 6 pg/mL with ongoing plasma hyperosmolality, further increases in urine osmolality cannot be achieved because of limits of the renal medullary gradient. Changes in blood volume inversely affect AVP secretion such that 8% to 10% of decrease in circulating blood volume stimulates AVP secretion and increases in intravascular volume inhibit AVP release. Baroreceptors in the carotid sinus and aortic arch (high-pressure baroreceptors) and in the atria and pulmonary venous circulation (low-pressure baroreceptors) relay pressure and volume information via the glossopharyngeal and vagus nerves, respectively, to the brain stem. These baroreceptors become activated when stretched by increases in intravascular volume, leading to inhibition of AVP secretion through fibers projecting from the brain stem to the PVN and SON of the hypothalamus. In addition, many other factors affect AVP secretion; it is stimulated by pain, nausea, stress, and various drugs and is inhibited by multiple factors.
Adequate water intake, governed by an intact thirst mechanism, is also regulated predominantly by changes in plasma osmolality, intravascular volume, and blood pressure. Thirst is consistently stimulated when plasma osmolality increases by 2% to 3% or when circulating blood volume decreases by 4% to 10%. Because the thresholds that trigger thirst are higher than those that trigger AVP secretion, adequate thirst becomes essential during pathologic states of AVP deficiency or insensitivity. Challenges in the management of adipsic diabetes insipidus, resulting from damage to thirst centers and to AVP-secreting neurons, highlight the critical role of thirst in the maintenance of plasma osmolality when AVP secretion or responsiveness is inadequate.
AVP exerts its antidiuretic action by binding to the X chromosome-encoded V2 vasopressin receptor (V2R), a G protein-coupled receptor on the basolateral membrane of renal collecting duct epithelial cells. After V2R activation, increased intracellular cyclic adenosine monophosphate (cAMP) mediates shuttling of the water channel aquaporin 2 (AQP-2) to the apical membrane of collecting duct epithelial cells, resulting in increased water permeability and antidiuresis ( Fig. 1 ).
Clinical disorders of water balance are common, and abnormalities in many steps involving AVP secretion and responsiveness have been described. This article focuses on the principal disorders of water balance, diabetes insipidus (DI), and the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Diabetes insipidus
DI results from the inability to reabsorb free water. Polyuria, polydipsia, and hypo-osmolar urine are the hallmarks of this disorder, although hypernatremia may be present, particularly in infants, at the time of diagnosis. DI can be central, due to deficiency of AVP, or nephrogenic, due to a defect in AVP action in the kidneys ( Box 1 ).
Central DI
Congenital
Structural malformations affecting the hypothalamus or pituitary
Autosomal dominant (or rarely recessive) mutations in the gene encoding AVP-NPII
Acquired
Primary tumors or metastases
Infection (eg, meningitis, encephalitis)
Histiocytosis
Granulomatous diseases
Autoimmune disorders (lymphocytic infundibuloneurohypophysitis)
Trauma
Surgery
Idiopathic
Nephrogenic DI
Congenital
X-linked: inactivating mutations in AVPR2
Autosomal: recessive or dominant mutations in AQP-2
Acquired
Primary renal disease
Obstructive uropathy
Metabolic causes (eg, hypokalemia, hypercalcemia)
Sickle cell disease
Drugs (eg, lithium, demeclocycline)
Prolonged polyuria of any cause
Nephrogenic DI (NDI) may be genetic or acquired. The genetic causes are inactivating mutations of the AVPR2 gene, located on the X chromosome (Xq28), or autosomal recessive or dominant mutations in the AQP-2 gene, located on chromosome 12 (12q13). Acquired NDI can be caused by various conditions, including some forms of primary renal disease, obstructive uropathy, hypokalemia, hypercalcemia, sickle cell disease, and drugs such as lithium and demeclocycline. Prolonged polyuria of any cause can also lead to some degree of NDI because of a reduction of tonicity in the renal medullary interstitium and a subsequent decrease in the gradient necessary to concentrate urine.
X-linked NDI (XNDI) is rare, affecting approximately 4 in 1,000,000 males worldwide, and it accounts for about 90% of the genetic causes of NDI. Of the 211 reported AVPR2 mutations causing XNDI, approximately half are missense, and 31 of these have been characterized functionally. Most AVPR2 missense mutations result in a translated but misfolded V2R protein that remains trapped in the endoplasmic reticulum. Pharmacologic chaperones can partially rescue the cell-surface expression and functional activity of misfolded mutant V2Rs that would otherwise be targeted for degradation.
Infants with congenital (X-linked or autosomal) NDI typically present within the first several weeks of life with nonspecific symptoms, such as fever, vomiting, dehydration, and growth failure, associated with polyuria and hypo-osmolar urine (50–100 mOsm/kg). Mental retardation of variable severity and intracerebral calcifications of the frontal lobes and basal ganglia can result from repeated episodes of dehydration if the condition remains untreated. Longstanding polyuria and polydipsia can lead to nonobstructive hydronephrosis, hydroureter, and megabladder. Thiazide diuretics, along with low sodium intake, were historically used to treat NDI, as this combination decreases glomerular filtration rate and results in decreased urine output. During the last 20 years, thiazide diuretics in combination with either amiloride or indomethacin have become the mainstay of congenital NDI treatment. In vitro studies have demonstrated that pharmacologic chaperones, which are cell permeable, nonpeptide small molecules, can restore the cell-surface expression and function of misfolded mutant V2Rs. One such compound is orally active, well tolerated, and effective in decreasing urine volume in adults with severe XNDI. Thus, pharmacologic chaperones represent a new, safe, and targeted therapy for XNDI caused by protein misfolding due to missense mutations of AVPR2 .
Central DI is rarely congenital and more frequently, acquired. Congenital central DI may be caused by structural malformations affecting the hypothalamus or by autosomal dominant or recessive mutations in the gene encoding AVP-NPII. The autosomal dominant causes are more common and result from heterozygous AVP-NPII gene mutations. The proposed mechanism for the dominant negative effect is that the heterozygous mutation disrupts the processing of the mutant precursor. The accumulation of this misfolded protein in the vasopressinergic neurons causes a gradual destruction of these neurons. In such patients, clinical DI usually develops several months to years after birth. A rare autosomal recessive form of central DI has been reported in association with a mutation in the AVP-NPII gene, resulting in a biologically inactive AVP.
Acquired forms of central DI occur in association with a variety of disorders in which there is destruction or degeneration of vasopressinergic neurons. Causes include primary tumors (eg, craniopharyngioma, germinoma) or metastases, infection (meningitis, encephalitis), histiocytosis, granuloma, vascular disorders, autoimmune disorders (lymphocytic infundibuloneurohypophysitis), and trauma or surgery. Idiopathic DI is a diagnosis of exclusion, and one that is made with decreasing frequency as a result of improved sensitivity of magnetic resonance imaging (MRI) of the brain and of tests for cerebral spinal fluid (CSF) and serum tumor markers.
The principal presenting sign of DI is polyuria, which, in addition to deficiency or impaired responsiveness to AVP, may result from an osmotic agent (eg, hyperglycemia in diabetes mellitus) or from excessive water intake (primary polydipsia). Hypernatremia usually does not occur if patients have an intact thirst mechanism, adequate access to fluids, and no additional ongoing fluid loss (eg, diarrhea). Infants with DI, in addition to polyuria and polydipsia, may be irritable and may have fever of unknown origin, growth failure secondary to inadequate caloric intake, and hydronephrosis. Older children may also have nocturia and enuresis. DI may not be apparent in patients with coexisting untreated anterior pituitary-mediated adrenal glucocorticoid insufficiency, as cortisol is required to generate normal free water excretion.
A diagnosis of DI can be made if simultaneous screening laboratory studies reveal hyperosmolality concurrent with urine that is inappropriately dilute. If DI is present, it is more likely to be uncovered by these screening tests if they are obtained as soon as possible after awakening and before any fluid intake (assuming that the patient has not consumed fluids overnight). However, because most patients with DI have intact thirst and can drink to prevent hyperosmolality and hypernatremia, a standardized water deprivation test is often necessary to make the diagnosis. The patient is monitored with serial measurements of weight, serum sodium level, serum osmolality, urine volume, and urine osmolality while being fasted and deprived of water for 8 to 10 hours. If urine osmolality greater than 750 mOsm/kg is achieved with any degree of water deprivation, DI can be excluded. The diagnosis of DI is established if serum osmolality rises above 300 mOsm/kg and urine osmolality remains below 300 mOsm/kg. Urine osmolality in the 300 to 750 mOsm/kg range during water deprivation may indicate partial DI. If DI is suspected, a plasma sample should be obtained for AVP radioimmunoassay. AVP or a synthetic analog (desmopressin) should then be administered to distinguish AVP deficiency from AVP unresponsiveness.
MRI of the brain, with particular attention to the hypothalamic-pituitary region, is indicated in patients with central DI. The posterior pituitary hyperintensity (“bright spot”) on T1-weighted magnetic resonance images is often absent in central DI. However, the bright spot can be absent in normal individuals, and conversely, children with central DI can have a normal bright spot at the time of diagnosis. Therefore, the presence of the bright spot does not establish neurohypophyseal integrity, and its absence does not always indicate central nervous system (CNS) pathology. In central DI patients with or without the posterior pituitary bright spot, an otherwise normal MRI warrants close follow-up with CSF tumor markers and cytology, serum tumor markers, and serial contrast-enhanced brain MRIs for early detection of an evolving occult hypothalamic-stalk lesion.
The management of central DI includes treating the primary disease, correction of a fluid deficit, if present, and normalization of urine output with desmopressin. This AVP analog has markedly reduced pressor activity in comparison with native AVP, has a prolonged half-life, and can be administered orally, intranasally, or by subcutaneous injection. In infancy, if polyuria is not excessive, DI may be best managed with fluid intake alone to avoid a potential risk of hyponatremia with desmopressin treatment.
Diabetes insipidus
DI results from the inability to reabsorb free water. Polyuria, polydipsia, and hypo-osmolar urine are the hallmarks of this disorder, although hypernatremia may be present, particularly in infants, at the time of diagnosis. DI can be central, due to deficiency of AVP, or nephrogenic, due to a defect in AVP action in the kidneys ( Box 1 ).
Central DI
Congenital
Structural malformations affecting the hypothalamus or pituitary
Autosomal dominant (or rarely recessive) mutations in the gene encoding AVP-NPII
Acquired
Primary tumors or metastases
Infection (eg, meningitis, encephalitis)
Histiocytosis
Granulomatous diseases
Autoimmune disorders (lymphocytic infundibuloneurohypophysitis)
Trauma
Surgery
Idiopathic
Nephrogenic DI
Congenital
X-linked: inactivating mutations in AVPR2
Autosomal: recessive or dominant mutations in AQP-2
Acquired
Primary renal disease
Obstructive uropathy
Metabolic causes (eg, hypokalemia, hypercalcemia)
Sickle cell disease
Drugs (eg, lithium, demeclocycline)
Prolonged polyuria of any cause
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