Arginine vasopressin (AVP)–mediated osmoregulatory disorders, such as diabetes insipidus (DI) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are common in the differential diagnosis for children with hypo- and hypernatremia and require timely recognition and treatment. DI is caused by a failure to concentrate urine secondary to impaired production of or response to AVP, resulting in hypernatremia. Newer methods of diagnosing DI include measuring copeptin levels; copeptin is AVP’s chaperone protein and serves as a surrogate biomarker of AVP secretion. Intraoperative copeptin levels may also help predict the risk for developing DI after neurosurgical procedures. Copeptin levels hold diagnostic promise in other pediatric conditions, too. Recently, expanded genotype and phenotype correlations in inherited DI disorders have been described and may better predict the clinical course in affected children and infants. Similarly, newer formulations of synthetic AVP may improve pediatric DI treatment. In contrast to DI, SIADH, characterized by inappropriate AVP secretion, commonly leads to severe hyponatremia. Contemporary methods aid clinicians in distinguishing SIADH from other hyponatremic conditions, particularly cerebral salt wasting. Further research on the efficacy of therapies for pediatric SIADH is needed, although some adult treatments hold promise for pediatrics. Lastly, expansion of home point-of-care sodium testing may transform management of SIADH and DI in children. In this article, we review recent developments in the understanding of pathophysiology, diagnostic workup, and treatment of better outcomes and quality of life for children with these challenging disorders.

Pediatric providers commonly encounter children with hypo- or hypernatremia.1  Arginine vasopressin (AVP)–dependent conditions, such as diabetes insipidus (DI) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are frequent in the differential diagnosis for children presenting with sodium or fluid abnormalities. Diagnosing DI and SIADH remains challenging, and prompt management is needed to prevent morbidity. Considerable advances in the understanding of pathophysiology, diagnostic processes, and treatment of children with these disorders have been made. Our aim is to review how to approach these disorders in children and highlight recent scientific developments.

AVP is derived from a preprohormone produced by magnocellular neurons within the paraventricular and supraoptic hypothalamic nuclei,24  along with its carrier protein, neurophysin II, and chaperone protein, copeptin.5  The magnocellular neurons terminate in the posterior pituitary stalk4  in which enough AVP is stored for a sustained antidiuretic effect of 5 to 10 days.6  AVP initiates its antidiuretic effect on renal epithelial cells of the collecting duct via the vasopressin-2 receptor (V2 receptor).2,3,7  Renal aquaporin channels facilitate water movement from the lumen into systemic circulation.3,711  AVP curtails water excretion and promotes renal water reabsorption.

Increasing serum osmolality, hypovolemia, and arterial hypotension stimulate AVP release. The organum vasculosum and the subfornical organ serve as central osmoreceptors, sensing disruptions in plasma osmolality through changes in cell volume.2,4,12,13  At a serum osmolality threshold of ∼280 mOsm/kg, AVP is released relative to the increasing osmolality.3,14  Osmolality is the most potent AVP stimulus, with a 1% change in serum osmolality stimulating AVP release.2,7,12,14  Children release more AVP compared with adults with the same osmolality.7,15  The sensation of thirst is governed by the ventromedial hypothalamic nucleus and triggered by increasing serum osmolality.14  AVP is also secreted in response to a 5% to 10% decrease in systemic pressure, as monitored by carotid sinus baroreceptors.2,3,7,14,16  Similarly, hypovolemia sensed by left atrium baroreceptors triggers AVP release.2,3,14,16  Lastly, nausea and emesis also induce AVP secretion via the emetic reflex itself by overriding the setpoint for AVP secretion and therefore inducing AVP release.2,3,14,17 

DI, defined by failure to concentrate urine secondary to serum osmolality increases, has a prevalence of 1 in 25 000 people.5  DI presents at variable ages on the basis of etiology.18  Of children with DI, 90% have central DI, whereas 10% have nephrogenic DI.5  Approximately 10% of all DI cases are heritable, with 90% being X-linked nephrogenic DI and 10% from autosomal dominant and recessive cases.

Central DI causes an inability to concentrate urine secondary to a loss of AVP production or secretion.8  It occurs after a loss of >80% of the sellar magnocellular neurons.5  In familial cases of central DI with accumulation of mutated neurophysin II, sellar anatomic abnormalities can be seen on autopsy with gliosis in the paraventricular and supraoptic hypothalamic nuclei.19,20  nephrogenic DI results from reduced or absent response to AVP with normal production and release.8 

Inherited Forms of Central DI

More than 70 different mutations in the AVP NPII gene have been implicated in central DI, (Table 1)21  occurring in the AVP, NPII, and signal sequences, but none have been identified in the copeptin moiety.22  Although the exact mechanism of a specific mutation’s effect remains unknown, accumulation of mutated AVP precursor in the endoplasmic reticulum likely impairs AVP processing and secretion.23  Autosomal dominant central DI is more common than autosomal recessive DI and typically presents after age 1, whereas autosomal recessive forms present 1 to 2 weeks after birth.10  However, wide variation in the age at presentation, even between children with the same genetic markers, suggests different rates of synthesis or clearance.5  Another genetic marker is a mutation in the PCSK1 gene, the product of which processes AVP.24 

TABLE 1

Comparison of DI Versus SIADH

Central DINephrogenic DISIADH
Common etiology in children    
 Inherited AVP NPII gene mutation21  X-linked V2 receptor mutation5  V2 receptor mutation22  
PCSK1 gene mutation24  Autosomal dominant and recessive aquaporin-2 channel mutations5,8  GNAS gene mutation98  
WFS1 or ZCD2 gene mutation25,26  TRPV4 gene mutation125  
Congenital hypopituitarism126  
 Acquired Idiopathic8,29  Drugs: lithium, demeclocycline, foscarnet, clozapine, amphotericin B, methicillin, rifampin68  Idiopathic12  
Brain malformations8,29 : septo-optic dysplasia, holoprosencephaly Hypercalcemia7  Cytotoxic agents85 : cyclophosphamide, vincristine 
Infiltrative8,29 : Langerhans cell histiocytosis, sarcoidosis, tuberculosis Hypokalemia7  Anticonvulsants85,94 : carbamazepine, oxcarbazepine 
Brain tumor8,29 : craniopharyngioma, germinoma Apparent mineralocorticoid excess40  Antidepressants85,95 : SSRIs, tricyclic 
Infection7,8 : meningitis, encephalitis Chronic renal disease: cystinosis, nephronophthisis, Bartter syndrome7,40  Pain medication85,104 : NSAIDs, narcotics 
Trauma7,8,29 : traumatic brain injury, hypoxic insult, surgery Osmotic diuresis: diabetes mellitus7  dDAVP104  
Supraventricular tachycardia127  Sickle cell disease128  Infection12,85,104 : febrile disease, pneumonia 
Anorexia nervosa129  Ureter obstruction130  Pulmonary disease12,85 : asthma, cystic fibrosis, bronchiolitis 
Bardet-Biedl disease131  Malignancies85 : lymphoma, carcinoma, Ewing sarcoma, cerebral tumors 
Trauma12,104 : traumatic brain injury, surgery 
HIV or AIDs12  
Signs and symptoms Hypernatremia Hypernatremia Hyponatremia 
Polyuria7 : >150 mL/kg per d in neonates, >100–110 mL/kg per d in children aged up to 2 y, >40–50 mL/kg per d in older children Polyuria rarely exceeds 3–4 L/d43  Oliguria101  
Polydipsia Polydipsia Euvolemia12  
Symptoms in infants68 : fever, vomiting, failure to gain weight Symptoms in all ages68 : recurrent fevers, vomiting, growth failure, mental retardation Symptoms85,104 : headache, nausea, vomiting, muscle cramps, lethargy, restlessness, confusion, seizures 
Symptoms in older children68 : disturbed sleep, lethargy, nocturia 
Symptoms in all ages68 : irritability, dehydration, potential seizures 
Differential Diabetes mellitus8  Diabetes mellitus8  Hyponatremia hypovolemia85,95 : cerebral salt wasting, GI loss, severe burns, acute sequestration into third spaces 
Nephrogenic DI8  Central DI8  Hyponatremia hypervolemia12,85,95 : congestive heart failure, cirrhosis, nephrotic syndrome, iatrogenic 
Renal disease8  Renal disease8  
Hypercalcemia8  Hypercalcemia8  
Iatrogenic16  Iatrogenic16  
Dehydration16  Dehydration16  
Primary polydipsia7  Primary polydipsia7  
Diagnostic criteria Serum glucose, calcium, potassium, SUN levels within normal limits8  Serum glucose, potassium, SUN levels within normal limits8 : hypercalcemia is a potential etiology Essential criteria103 : effective serum osmolality <275 mOsm/kg; urine osmolality >100 mOsm/kg; clinical euvolemia; urine sodium concentration > 30 mmol/L; absence of adrenal, thyroid, pituitary, or renal insufficiency; no recent diuretic agents 
Current protocol: water deprivation testing8 : serum osmolality >300 mOsm/kg with simultaneous urine osmolality <300 mOsm/kg, dDAVP increases urine osmolality >750 mOsm/kg Current protocol: water deprivation testing8 : serum osmolality >300 mOsm/kg with simultaneous urine osmolality <300 mOsm/kg, dDAVP administration fails to increase urine osmolality Supplemental criteria103 : serum uric acid level <0.24 mmol/L, serum urea level <3.6 mmol/L, failure to correct hyponatremia after 0.9% saline infusion, fractional sodium excretion >0.5%, fractional urea excretion >55%, fractional uric acid excretion >12%, correction of hyponatremia through fluid restriction 
Future potential protocols: hypertonic saline-induced serum copeptin50 Future potential protocol: elevated baseline copeptin measurement >20 pmol/L48  
Water deprivation test coupled with serum copeptin measurements56 : <2.2 pmol/L (central DI), 2.2–5 pmol/L (central DI or primary polydipsia), >5–20 pmol/L (primary polydipsia), >20 pmol/L (nephrogenic DI) 
Central DINephrogenic DISIADH
Common etiology in children    
 Inherited AVP NPII gene mutation21  X-linked V2 receptor mutation5  V2 receptor mutation22  
PCSK1 gene mutation24  Autosomal dominant and recessive aquaporin-2 channel mutations5,8  GNAS gene mutation98  
WFS1 or ZCD2 gene mutation25,26  TRPV4 gene mutation125  
Congenital hypopituitarism126  
 Acquired Idiopathic8,29  Drugs: lithium, demeclocycline, foscarnet, clozapine, amphotericin B, methicillin, rifampin68  Idiopathic12  
Brain malformations8,29 : septo-optic dysplasia, holoprosencephaly Hypercalcemia7  Cytotoxic agents85 : cyclophosphamide, vincristine 
Infiltrative8,29 : Langerhans cell histiocytosis, sarcoidosis, tuberculosis Hypokalemia7  Anticonvulsants85,94 : carbamazepine, oxcarbazepine 
Brain tumor8,29 : craniopharyngioma, germinoma Apparent mineralocorticoid excess40  Antidepressants85,95 : SSRIs, tricyclic 
Infection7,8 : meningitis, encephalitis Chronic renal disease: cystinosis, nephronophthisis, Bartter syndrome7,40  Pain medication85,104 : NSAIDs, narcotics 
Trauma7,8,29 : traumatic brain injury, hypoxic insult, surgery Osmotic diuresis: diabetes mellitus7  dDAVP104  
Supraventricular tachycardia127  Sickle cell disease128  Infection12,85,104 : febrile disease, pneumonia 
Anorexia nervosa129  Ureter obstruction130  Pulmonary disease12,85 : asthma, cystic fibrosis, bronchiolitis 
Bardet-Biedl disease131  Malignancies85 : lymphoma, carcinoma, Ewing sarcoma, cerebral tumors 
Trauma12,104 : traumatic brain injury, surgery 
HIV or AIDs12  
Signs and symptoms Hypernatremia Hypernatremia Hyponatremia 
Polyuria7 : >150 mL/kg per d in neonates, >100–110 mL/kg per d in children aged up to 2 y, >40–50 mL/kg per d in older children Polyuria rarely exceeds 3–4 L/d43  Oliguria101  
Polydipsia Polydipsia Euvolemia12  
Symptoms in infants68 : fever, vomiting, failure to gain weight Symptoms in all ages68 : recurrent fevers, vomiting, growth failure, mental retardation Symptoms85,104 : headache, nausea, vomiting, muscle cramps, lethargy, restlessness, confusion, seizures 
Symptoms in older children68 : disturbed sleep, lethargy, nocturia 
Symptoms in all ages68 : irritability, dehydration, potential seizures 
Differential Diabetes mellitus8  Diabetes mellitus8  Hyponatremia hypovolemia85,95 : cerebral salt wasting, GI loss, severe burns, acute sequestration into third spaces 
Nephrogenic DI8  Central DI8  Hyponatremia hypervolemia12,85,95 : congestive heart failure, cirrhosis, nephrotic syndrome, iatrogenic 
Renal disease8  Renal disease8  
Hypercalcemia8  Hypercalcemia8  
Iatrogenic16  Iatrogenic16  
Dehydration16  Dehydration16  
Primary polydipsia7  Primary polydipsia7  
Diagnostic criteria Serum glucose, calcium, potassium, SUN levels within normal limits8  Serum glucose, potassium, SUN levels within normal limits8 : hypercalcemia is a potential etiology Essential criteria103 : effective serum osmolality <275 mOsm/kg; urine osmolality >100 mOsm/kg; clinical euvolemia; urine sodium concentration > 30 mmol/L; absence of adrenal, thyroid, pituitary, or renal insufficiency; no recent diuretic agents 
Current protocol: water deprivation testing8 : serum osmolality >300 mOsm/kg with simultaneous urine osmolality <300 mOsm/kg, dDAVP increases urine osmolality >750 mOsm/kg Current protocol: water deprivation testing8 : serum osmolality >300 mOsm/kg with simultaneous urine osmolality <300 mOsm/kg, dDAVP administration fails to increase urine osmolality Supplemental criteria103 : serum uric acid level <0.24 mmol/L, serum urea level <3.6 mmol/L, failure to correct hyponatremia after 0.9% saline infusion, fractional sodium excretion >0.5%, fractional urea excretion >55%, fractional uric acid excretion >12%, correction of hyponatremia through fluid restriction 
Future potential protocols: hypertonic saline-induced serum copeptin50 Future potential protocol: elevated baseline copeptin measurement >20 pmol/L48  
Water deprivation test coupled with serum copeptin measurements56 : <2.2 pmol/L (central DI), 2.2–5 pmol/L (central DI or primary polydipsia), >5–20 pmol/L (primary polydipsia), >20 pmol/L (nephrogenic DI) 

GI, gastrointestinal; SSRI, selective serotonin reuptake inhibitors.

Type 1 Wolfram syndrome, an autosomal recessive condition caused by loss-of-function mutation in the WFS1 gene or missense mutation in the ZCD2 gene,25,26  is characterized by central DI due to abnormal AVP processing or neuronal migration,25  diabetes mellitus, and optic degeneration.22 

Septo-optic dysplasia, in both its spontaneous and inherited forms, can result in central DI8,27  secondary to dysfunction of the central osmoreceptors.28  In children with central DI, the prevalence of septo-optic dysplasia is 15%.29 

Acquired Forms of Central DI

At least 50% of acquired central DI forms are initially diagnosed as idiopathic.30  However, Werny et al29  suggest an alternate diagnosis is identified in almost 20% of these children and within 3 years of that diagnosis. One such diagnosis is autoimmune-mediated DI. Maghnie et al31  identified AVP-secreting cell antibodies AVPc-Abs in 75% of children with idiopathic central DI. However, these nonspecific antibodies have also been found in affected patients with other definitive causes of DI, such as Langerhans cell histiocytosis, germinomas, and postoperative DI.31,32  The autoimmune mechanism is strengthened by a temporal relationship between viral infection and onset of central DI in ∼25% of idiopathic cases.30  Additional autoimmune conditions associated with central DI secondary to hypophysitis include rabphilin-3A autoantibodies and IgG4-related systemic syndrome.33,34 

Langerhans cell histiocytosis is identified in 12% of children with acquired central DI.29  Typically, other symptoms of Langerhans cell histiocytosis precede those of central DI by 1 year.35  Central DI is its most common central nervous system (CNS) manifestation,36  occurring in 17% to 25% of children with the disease,35  most likely because of hypothalamic infiltration and subsequent scarring.

Brain tumors are another common cause of acquired central DI. Werny et al29  noted 35% of children presenting with central DI were ultimately found to have brain tumors. Central DI can present because of tumor invasion or postoperatively after debulking surgeries.5,37,38  Craniopharyngiomas and germinomas are the most common brain tumors that invade the sella and cause DI.5,39  Because these tumors are slow growing, DI may manifest before identification of the tumor on imaging, with a median 1 year lag in time between presentation of DI to germinoma diagnosis.30  Thus, MRIs are recommended every 3 to 6 months postdiagnosis of acquired idiopathic DI for at least 2 years if, on initial MRI, there is a widened pituitary stalk.5 

Forms of Nephrogenic DI

Medications and electrolyte abnormalities commonly cause nephrogenic DI (Table 1).7,8  Renal disease and obstruction can also be implicated.40  The most common form of inherited nephrogenic DI is X-linked, caused by a V2 receptor mutation.5  Less commonly, there are autosomal dominant and recessive mutations in the aquaporin-2 channel known to cause nephrogenic DI.5,8 

Similar to central DI, children with nephrogenic DI present with polydipsia and polyuria.41  They often prefer cold water over other beverages.39  Unusual water-seeking behaviors may occur from puddles, vases,39  or toilets.7  Infants or children with developmental delay may experience unintentional fluid restriction, leaving them especially vulnerable to hypernatremia.42  Children with DI may have primary or secondary nocturnal enuresis.8,39  Children with nephrogenic DI typically have less severe polyuria and polydipsia compared with those with central DI.43  Not all children with central DI have polydipsia because some lack thirst (adipsia) because of midline CNS abnormalities44  or autoantibodies against45  central osmoreceptors.42,46  Many cases of central DI are due to intracranial tumors, so symptoms, such as headaches, vomiting, growth retardation, and fatigue should be assessed.8,30  However, growth retardation and poor weight gain may stem from a preference for water over food8  and not be associated with an intracranial tumor.5 

In hospitalized children, the incidence of hypernatremia, at a serum sodium level >150 mEq/L, has been estimated at 1.4%.47  Hypernatremia can be attributed to excessive fluid loss, such as gastroenteritis or solute diuresis, decreased fluid intake, or inappropriate salt intake.47  Inappropriate salt intake rarely results from poisoning but can inadvertently occur with administration of 0.9% saline in children with DI because the concentration of salt overwhelms the child’s ability to excrete it, given that urine osmolality is typically low. A laboratory workup may help rule out these other causes. Serum glucose, calcium, potassium, and serum urea nitrogen (SUN) levels within normal limits should raise clinical suspicion of DI.8  Serum osmolality levels >300 mOsm/kg and urine osmolality levels <300 mOsm/kg suggest DI.8  Primary polydipsia also presents with polydipsia and polyuria, although it may cause slight hyponatremia.7  It is characterized by inappropriate fluid intake,48,49  which downregulates AVP secretion43  and aquaporin-2 channels.49  The water deprivation test is the current gold standard to establish the child’s ability to concentrate urine.8  During testing, the child abstains from all oral and IV fluids with hourly serum sodium and osmolality, urine osmolality, specific gravity, and urine volume measurements.8  At many institutions, a urine osmolality level >1000 or >600 mOsm/kg and stable for 2 voids rule out DI; the patient may instead have primary polydipsia.8,49  If the serum osmolality level is >300 mOsm/kg and the urine osmolality level is <300 mOsm/kg, the child is diagnosed with DI.5  However, diagnostic accuracy of the water deprivation test is only ∼70%,49  perhaps because of difficulty in diagnosing partial DI and downregulation of AVP production in patients with polydipsia.43,49,50  To differentiate central from nephrogenic DI, administration of deamino-8-D-arginine vasopressin (dDAVP) will increase urine osmolality of >750 mOsm/kg only in central DI.8 

Tumor markers α-fetoprotein and human chorionic gonadotrophin used to screen for neoplasms7  and an MRI of the pituitary gland are recommended when a child is diagnosed with central DI.5,29  Although not specific to central DI, the degree of a posterior pituitary hypointensity correlates with duration of transient central DI.8,51,52  A thickened pituitary stalk, seen in 33% of pediatric patients with DI, is associated with Langerhans cell histiocytosis, germinomas, and hypophysitis.5,53 

The copeptin assay has become more widely available in clinical chemistry laboratories and is gaining popularity because of the stability of this peptide in plasma.54  When it was compared with serum AVP, Balanescu et al55  found copeptin more closely correlated with plasma osmolarity, rendering it a better diagnostic marker for vasopressin-mediated disorders. Pediatric copeptin reference ranges have not been formally established; however, levels in healthy, non–water-deprived children likely range from 2.4 to 9.0 pmol/L.56,57  Copeptin values vary slightly between sexes in adults58  and neonates.59  They do not vary with age in adults and are thought to be similar to adult basal levels within a day of birth if the neonate is healthy.58,60 

The role of copeptin in diagnosing osmoregulatory disorders has been studied more in adults than children. Fenske et al48,50  found the change in ratio of copeptin to serum sodium concentrations over time improved the diagnostic accuracy of the water deprivation test, which was challenged in a later study. Stimulated plasma copeptin levels by using a hypertonic saline infusion were used to more accurately diagnose DI than the water deprivation test, with a diagnostic accuracy of 96.5%50  and may replace the water deprivation test at some institutions.61 

Copeptin is currently used in pediatrics to quantify neonatal stress, such as asphyxia and hypothermia.6265  Other studies have analyzed the role of copeptin as a prognostic biomarker in pediatric conditions, as reviewed in Table 2. However, in the acute setting, a cautious interpretation of serum copeptin should be made because of potential multifactorial influences on AVP secretion.66  There have been limited studies on the role of copeptin in pediatric osmoregulatory disorders. Tuli et al56  analyzed water deprivation-induced copeptin in the differential of polyuria-polydipsia syndrome, proposing cutoffs of copeptin values for diagnosis of central DI, partial central DI, primary polydipsia, and nephrogenic DI in children. An elevated baseline copeptin value could be used to diagnose nephrogenic DI without a water deprivation test or hypertonic saline bolus,48,56  as was done in an infant presenting with polyuria-polydipsia and poor weight gain.67  Copeptin levels normalized after successful treatment in the infant, suggesting copeptin levels could indicate responsiveness to treatment of polyuria-polydipsia syndromes.

TABLE 2

Potential Pediatric Applications of Copeptin as a Biomarker

ClassificationProposed MechanismConditions
Osmoregulatory disorders Fluctuations in serum osmolality induce AVP secretion. DI (central and nephrogenic)56,67  
Polyuria-polydipsia syndrome56,67  
Nocturnal enuresis132,133  
Acute postsurgical AVP disruptions 
Critical illness In adults, acute phase cytokines can elevate copeptin levels.134  Pneumonia and complications57,135,136  
Traumatic brain injury and prognosis137  
Post–cardiac surgery complications138  
Children with high mortality risk139  
Perinatal illness States of physical stress such as decreased serum pH and asphyxia secondary to delivery or other etiologies likely induce AVP and copeptin secretion.140  Vaginal delivery versus cesarean delivery140142  
Asphyxia64,140  
Mechanical ventilation63  
Hypoxic-ischemic encephalopathy143  
Maternal preeclampsia144,145  
Fetal acidosis140,146  
Other pediatric conditions — Type 1 diabetes and complications147,148  
Obesity149  
Cystic fibrosis150  
Primary hypertension151  
Efficacy of treatment in postural orthostatic tachycardia syndrome152,153  
Febrile seizure154,155  
Maltreatment156  
Psychological stress157  
ClassificationProposed MechanismConditions
Osmoregulatory disorders Fluctuations in serum osmolality induce AVP secretion. DI (central and nephrogenic)56,67  
Polyuria-polydipsia syndrome56,67  
Nocturnal enuresis132,133  
Acute postsurgical AVP disruptions 
Critical illness In adults, acute phase cytokines can elevate copeptin levels.134  Pneumonia and complications57,135,136  
Traumatic brain injury and prognosis137  
Post–cardiac surgery complications138  
Children with high mortality risk139  
Perinatal illness States of physical stress such as decreased serum pH and asphyxia secondary to delivery or other etiologies likely induce AVP and copeptin secretion.140  Vaginal delivery versus cesarean delivery140142  
Asphyxia64,140  
Mechanical ventilation63  
Hypoxic-ischemic encephalopathy143  
Maternal preeclampsia144,145  
Fetal acidosis140,146  
Other pediatric conditions — Type 1 diabetes and complications147,148  
Obesity149  
Cystic fibrosis150  
Primary hypertension151  
Efficacy of treatment in postural orthostatic tachycardia syndrome152,153  
Febrile seizure154,155  
Maltreatment156  
Psychological stress157  

—, not applicable.

For DI, first-line treatment is unrestricted water access and a low sodium diet, which may be particularly effective for children with nephrogenic DI (Table 3).8,68  Adjustments may be necessary to achieve proper hydration and nutritional status. Intermittent catheterization or cystostomy should be introduced for postvoiding residual volume.69  However, some children with central DI may require synthetic vasopressin (desmopressin or dDAVP) if their polyuria persists. dDAVP has a longer duration of action8,44  than endogenous AVP, with a half-life of 3.5 hours.5  Oral or intranasal formulations are preferred in older pediatric patients because of better compliance and absorption.5,70  The major risks of dDAVP are hyponatremia and potential extrapontine myelinolysis in the presence of multidrug therapy if hypernatremia is rapidly reversed.71  Thus, the first dose should be small and then increased to find the child’s therapeutic window.7  Dosing is based on symptom control, not age or weight.8,44 

TABLE 3

Review of Pharmacologic Therapy for Central DI

TherapyAverage DoseMechanism of Action
dDAVP: oral, intranasal, subcutaneous7,8  Oral: 50–200 μg/d (2–3 doses; child), 100–500 μg/d (2–3 doses; adolescent) Synthetic vasopressin activates V2 receptor 
Intranasal: 2.5–10 μg/d (2–3 doses; child), 10–20 μg/d (2–3 doses; adolescent) 
Subcutaneous:0.01 μg/d (1 dose; infant), 0.3–0.5 μg/d (1 dose; child), 0.5–1 μg/d (1 dose; adolescent) 
Thiazide diuretics8  Hydrochlorothiazide: 1–3 mg/kg per d (in up to 2 doses) Inhibit sodium chloride cotransporter to reduce reabsorption of sodium in distal tubule; consequently, it enacts sodium and water reabsorption in the proximal tubule, so less water dilutes the filtrate in the ascending loop of Henle 
Chlorothiazide: 5–10 mg/kg/d (in 2–3 doses) 
Desmopressin lyophilizate8  1–2 μg/kg per d Synthetic vasopressin activates V2 receptor 
Amiloride8  0.3–0.625 mg/kg per d Potassium-sparing diuretic 
Chlorpropamide7,a,b <150–350 mg/d Potentiates secretion of AVP, increase reactivity of V2 receptor to basal levels of endogenous AVP 
Carbamazepine7,a,b 200 mg/d (up to 2 doses per d) Increases reactivity of V2 receptor to basal levels of endogenous AVP 
TherapyAverage DoseMechanism of Action
dDAVP: oral, intranasal, subcutaneous7,8  Oral: 50–200 μg/d (2–3 doses; child), 100–500 μg/d (2–3 doses; adolescent) Synthetic vasopressin activates V2 receptor 
Intranasal: 2.5–10 μg/d (2–3 doses; child), 10–20 μg/d (2–3 doses; adolescent) 
Subcutaneous:0.01 μg/d (1 dose; infant), 0.3–0.5 μg/d (1 dose; child), 0.5–1 μg/d (1 dose; adolescent) 
Thiazide diuretics8  Hydrochlorothiazide: 1–3 mg/kg per d (in up to 2 doses) Inhibit sodium chloride cotransporter to reduce reabsorption of sodium in distal tubule; consequently, it enacts sodium and water reabsorption in the proximal tubule, so less water dilutes the filtrate in the ascending loop of Henle 
Chlorothiazide: 5–10 mg/kg/d (in 2–3 doses) 
Desmopressin lyophilizate8  1–2 μg/kg per d Synthetic vasopressin activates V2 receptor 
Amiloride8  0.3–0.625 mg/kg per d Potassium-sparing diuretic 
Chlorpropamide7,a,b <150–350 mg/d Potentiates secretion of AVP, increase reactivity of V2 receptor to basal levels of endogenous AVP 
Carbamazepine7,a,b 200 mg/d (up to 2 doses per d) Increases reactivity of V2 receptor to basal levels of endogenous AVP 
a

Not recommended for use in children because of adverse side effects.

b

Pediatric dosing not fully established.

Treating infants with central DI poses additional challenges. Because they rely on fluids almost exclusively for caloric intake, using dDAVP may quickly cause fluid overload and hyponatremia,68,72  especially when administered orally.73  Buccally-administered intranasal or subcutaneous dDAVP can be diluted into smaller doses, which lowers the risk of serum sodium fluctuations.8,7274  However, many providers choose thiazide diuretics for infants. Thiazide diuretics, in combination with low renal solute formula, breast milk, which is naturally low in solute, or amiloride, optimize serum osmolality management.68,72,75  Infants treated with thiazide diuretics may develop slow weight gain and hypercalcemia.75,76  Desmopressin lyophilizate, a newer treatment, melts sublingually and has greater bioavailability than dDAVP tablets with comparable efficacy, but may cost more.77,78  Smaller doses make it a potential treatment option for infants.8,79 

Adipsic central DI should be managed with dDAVP and a fixed fluid regimen based on the child’s weight.4,8,44 

If nephrogenic DI cannot be managed with appropriate water and sodium intake, children may be treated with thiazide diuretics and secondary68  nonsteroidal antiinflammatory drug (NSAID) or amiloride use.80  NSAIDs increase proximal tubule water reabsorption when coupled with thiazides.8  It may be effective because COX-2 is known to be upregulated in patients with nephrogenic DI.81  However, because of the gastrointestinal side effects of NSAIDs and concerns for infant use, amiloride is favored.68,80,82  Sildenafil citrate increases aquaporin-2 trafficking to the apical membrane and could be effective in certain genotypes.83 

SIADH is one of the most prevalent causes of hyponatremia in children.84  It is the major cause of euvolemic hyponatremia in children.85  The prevalence of SIADH varies with etiology. For example, Seetharam et al86  reported a prevalence of ∼10% in pediatric patients undergoing chemotherapy for acute lymphoblastic leukemia, whereas Hasegawa et al87  reported a prevalence of ∼30% in hospitalized children with acute febrile illnesses.

Secretion of AVP outside an osmotic or nonosmotic stimulation is termed SIADH.88  Elevated atrial natriuretic peptide levels89  may compensate for the increased secretion of AVP and the resulting lowering of aldosterone, causing hyperosmolar urine and euvolemia.12  Over time, the phenomenon of escape from antidiuresis occurs, in which oversecretion of AVP eventually downregulates V2 receptors and the aquaporin-2 channel.90 

The heterogeneity of SIADH is represented in its etiologies. Different classes of pharmacologic agents are associated with SIADH in children,12  including antineoplastic agents,9193  anticonvulsants,91,94  antidepressants,91  antipsychotics, and pain medications.91  Although some pharmacologic agents induce a hyponatremic state within hours,93  SIADH secondary to selective serotonin reuptake inhibitors can develop a few days after administration.95  Shepshelovich et al91  reported an increase in incidence but not severity of SIADH with concurrent use of multiple SIADH-associated drugs. Malignancies can result in ectopic or inappropriate endogenous AVP production,12,96  most commonly lymphoma, Ewing sarcoma, and carcinoma of the lung, bladder, duodenum, pancreas, and thymus.85  Surgeries can stimulate inappropriate AVP release in children from severe pain, nausea, general anesthesia, and direct tissue trauma in the case of neurosurgical procedures.12,85 

Up to 20% of patients diagnosed with SIADH have less-than-expected AVP secretion for degree of hyponatremia,97  which could be confirmed by serum copeptin. Thus, the inherited form of SIADH, nephrogenic SIADH, should be suspected in the child.85  Additionally, nephrogenic SIADH should be in the differential diagnosis for infants with hyponatremia. Children affected by this disorder may present as infants with signs and symptoms of SIADH, despite less AVP secretion than what is found in central SIADH.97  It is an X-linked disorder caused by a mutation in the V2 receptor rendering it constitutively active.12,95,97  Biebermann et al98  recently reported a novel missense mutation of GNAS in 2 pediatric patients presenting with multisystem disease including nephrogenic SIADH.

Up to 20% of hospitalized children may have hyponatremia, defined as serum sodium levels <135 mEq/L.99  Others propose a wide range in prevalence between 1.4% and 45%, depending on the inclusion criteria for hyponatremia. Children and neonates are more likely to develop hospital-acquired hyponatremia than present with it.84,100 

Causes of hyponatremia can be divided into states of fluid load: hypovolemia, euvolemia, and hypervolemia. Cerebral salt wasting is a prevalent cause of hypovolemic hyponatremia in children,85  often because of traumatic brain injury or neurosurgical procedures.101  In cerebral salt wasting, excessive sodium excretion may be due to reduced sodium reabsorption secondary to impaired sympathetic innervation,12,95  whereas the role of atrial natriuretic peptide remains controversial.12,95,101  Other causes of hypovolemic hyponatremia are gastrointestinal conditions, such as gastroenteritis, severe burns, and acute sequestration into third spaces including sepsis.85  A urine sodium concentration <10 mEq/L differentiates these conditions from cerebral salt wasting, which has a urine sodium concentration >20 mEq/L.85 

Hypervolemic hyponatremia occurs in congestive heart failure, cirrhosis, and nephrotic syndrome.12,85  The hypervolemia manifests in extravascular edema.12  Reduced effective circulating volume stimulates AVP secretion.12 

Other causes of hyponatremia in children include ecstasy and other substances, which initiate inappropriate secretions of AVP, and endurance exercise from sweating and high fluid intake.102 

SIADH is characterized by euvolemic hyponatremia in the presence of impaired urinary dilution.12  SIADH is usually transient97  in pediatric patients but may be chronic when secondary to CNS or pulmonary conditions.85  Severe hyponatremia can cause hyponatremic encephalopathy,102,103  with seizures, coma, paralysis, and even death, as excess water diffuses via an osmotic gradient into brain cells.85  Furthermore, children have a higher likelihood of brain herniation with hyponatremia because of their larger brain-to-skull volume ratio.12 

It remains difficult to distinguish between cerebral salt wasting and SIADH. Children with CNS disease may be more likely to have cerebral salt wasting than SIADH.104  In postoperative hyponatremic states, age <7 years, and female sex were associated with cerebral salt wasting versus SIADH.105  Clinical signs and symptoms of cerebral salt wasting in children include polyuria, hypovolemia, hyponatremia, and elevated potassium excretion.101  Signs of dehydration in children, including dry mucous membranes, poor skin turgor, and a sunken fontanelle in infants, should raise suspicion for cerebral salt wasting.12,106  It is typically transient in children, lasting 10 to 20 days.101 

Differentiating cerebral salt wasting from SIADH can be particularly difficult in children. Low urine output in children suggests SIADH over cerebral salt wasting.106  SIADH is a diagnosis of elimination, but essential criteria exist.103  Supplemental criteria raise clinical suspicion for SIADH in children if not all essential criteria are met. Elevated fractional uric acid excretion has been used in adults with SIADH to differentiate it from cerebral salt wasting, but this trend is not confirmed in children.12,107  Serum copeptin is thought to have low diagnostic value in hyponatremia, given the breadth of conditions causing hyponatremia.66  Hypovolemia in cerebral salt wasting typically presents with a high urine output, tachycardia, hypotension, increased SUN, creatinine, and serum uric acid concentrations.85,102  Normal fractional uric acid excretion in the clinical setting of mild hyponatremia is highly suggestive of reset osmostat SIADH, a condition in which a smaller physiologic stimulus than normal is the threshold for AVP secretion.12,108 

With many hospitalized children at risk for hyponatremia, prevention with isotonic maintenance fluids is important.85 

If hyponatremia presents with neurologic manifestations, it should be managed with hypertonic saline and serial monitoring of serum sodium.12  Reversal of hyponatremia needs to be monitored carefully to prevent overcorrection and ensuing demyelination.109 

First-line therapy of SIADH is fluid restriction,85  particularly postoperatively.110,111  However, fluid restriction is burdensome on infants because they rely on fluid intake for calories; higher caloric milk concentrations are often useful.97  Other management options are pharmacologic agents (Tables 4 and 5).112  In a prospective study on adults with SIADH, researchers found oral urea to be similarly tolerated and effective when compared with vaptans.113  Vaptans are approved for euvolemic and hypervolemic hyponatremia in adults.114  Both tolvaptan, the oral form, and conivaptan, the intravenous form, have been used to manage SIADH in pediatric patients, as reported in case studies; however, more research is required to study the efficacy and safety in children.106,107,115,116  For drug-induced SIADH, cessation of the causative agent may suffice.

TABLE 4

Review of Pharmacologic Therapy for SIADH

TherapyTypical DoseMechanism of Action
Furosemide112,158  0.5–2 mg/kg dose Loop diuretic that blocks sodium, chloride, and potassium reabsorption and improves free water excretion 
Oral urea159  0.1 g/kg per d (in 4 doses) Decreases natriuresis and enhances free water excretion 
Maximum dose of 2 g/kg per d or total dose of 60 g/d 
Vaptans85,a Tolvaptan: 0.14–0.28 mg/kg/d (from alternate days to up to 2 doses)106,107  Competitively bind V2 receptor, blocking the insertion of the aquaporin-2 channel, enhancing urine dilution, and improving serum sodium 
0.22–0.8 mg/kg/d115  
Conivaptan: 10–30 mg/d (continuous administration over 24 h)116  
Demeclocycline, lithium85,a,b — Antagonize the V2 receptor 
SGLT-2 Inhibitor160,a — Increases glucosuria and free water clearance 
TherapyTypical DoseMechanism of Action
Furosemide112,158  0.5–2 mg/kg dose Loop diuretic that blocks sodium, chloride, and potassium reabsorption and improves free water excretion 
Oral urea159  0.1 g/kg per d (in 4 doses) Decreases natriuresis and enhances free water excretion 
Maximum dose of 2 g/kg per d or total dose of 60 g/d 
Vaptans85,a Tolvaptan: 0.14–0.28 mg/kg/d (from alternate days to up to 2 doses)106,107  Competitively bind V2 receptor, blocking the insertion of the aquaporin-2 channel, enhancing urine dilution, and improving serum sodium 
0.22–0.8 mg/kg/d115  
Conivaptan: 10–30 mg/d (continuous administration over 24 h)116  
Demeclocycline, lithium85,a,b — Antagonize the V2 receptor 
SGLT-2 Inhibitor160,a — Increases glucosuria and free water clearance 

—, not applicable.

a

Pediatric dosing not fully established.

b

Not recommended for use in children because of adverse side effects.

TABLE 5

Pathophysiology of DI and SIADH

Central DISIADH
Secretion of AVP Decrease Increase 
Insertion of aquaporin-2 channel in collecting ducts Decrease Increase 
Effect on water reabsorption Decrease Increase 
Resulting plasma sodium concentration Increase Decrease 
Central DISIADH
Secretion of AVP Decrease Increase 
Insertion of aquaporin-2 channel in collecting ducts Decrease Increase 
Effect on water reabsorption Decrease Increase 
Resulting plasma sodium concentration Increase Decrease 

Nephrogenic syndrome of inappropriate antidiuresis may be treated with demeclocycline, lithium, and other pharmacologic agents that antagonize the mechanism of action of the V2 receptor.95,97  However, these agents are falling out of favor in pediatrics because of other therapeutic options.85 

Hypovolemic and hypervolemic hyponatremia can be managed with isotonic fluids and diuretics with fluid restriction, respectively.85 

Neurosurgical procedures in children can acutely disrupt vasopressin secretion, often in a triple response consisting of transient DI, subsequent SIADH, and a final phase of DI or a return to normal AVP release.117  Postsurgical edema or perioperative trauma causes axonal shock, resulting in the initial central DI phase, lasting up to 2 days.37,41,118  The second SIADH phase, lasting 2 to 10 days, occurs from atrophying cells releasing stored AVP.41  The final phase of permanent DI occurs if >80% of magnocellular neurons were injured and thus cannot form new AVP. Kruis et al37  reported a triple response in 22.5% of children undergoing surgery in the sellar area. In children, increased surgery time likely raises the risk of developing a triphasic response.119  Risk factors for permanent postoperative DI in children include early onset of the triphasic response, complications independent of osmoregulation, and large fluctuations in postoperative serum sodium.37  Treating initial DI with vasopressin may mask the transition to SIADH,41  which is why some providers prefer exclusive fluid administration initially.120  During the SIADH phase, fluid restriction may suffice; however, a single tolvaptan dose for children may be needed for severe hyponatremia.111,120  Also, even children with preoperative DI can still experience the triple phase.37  Children undergoing surgery in the sellar area need to be closely monitored for changes in serum osmolality to prevent acute shifts in serum sodium concentration.

Further genetic testing and improved understanding of genotype and phenotype correlations in different AVP-associated mutations may improve clinical management of various subpopulations of DI.121  For example, Patti et al121  recently described a single nucleotide variant in the AVP NPII gene predicting later DI onset at a median of 120 months. Greater use of molecular analysis has the potential to enhance genetic counseling and diagnostic accuracy while limiting the use of unnecessary testing.

Copeptin holds promise for improving identification and diagnosis in children with hyper- and hypoosmolar states. Further work is needed to establish pediatric references ranges throughout childhood. Serum copeptin concentrations coupled with the hypertonic saline infusion rather than the water deprivation test could improve diagnostic accuracy of polyuria-polydipsia syndrome and remove the burden of the water deprivation test; however, close monitoring would be needed in the pediatric population. Postoperative copeptin values may promote earlier recognition and diagnosis of DI. In adults, low postoperative copeptin values predicted DI onset.122  Similar pediatric studies are needed, including those using intraoperative copeptin to predict DI or indicate shifts in the triphasic response, allowing physicians to change management preemptively.

Point-of-care sodium devices are needed to help parents and children better monitor fluctuations at home, especially in children with adipsia and DI.123  With caregiver education on use of the device, proper interpretation of results, and appropriate subsequent management, expansion of at-home point-of-care sodium may reduce burden on the health care system and improve patient outcomes. Green et al found a strong correlation between point-of-care sodium analyzer and laboratory sodium values. Additionally, use of at-home devices resulted in appropriate treatment outcomes in >90% of cases of DI.124 

Pediatric vasopressin-dependent disorders remain challenging to diagnose and treat. Early recognition and prompt management of DI and SIADH can improve quality of life and reduce potential risks associated with serum sodium concentration abnormalities. Improved diagnostic tools, such as identification of genetic markers, copeptin, and point-of-care sodium could give providers insight into disease progress and prognosis, moving toward better outcomes and quality of life for children and their families.

Ms Driano conceptualized the idea and wrote the first draft; Drs Creo and Lteif assisted in refining the concepts and provided guidance throughout the project; and all authors reviewed and approved the final manuscript as submitted.

FUNDING: No external funding.

     
  • AVP

    arginine vasopressin

  •  
  • CNS

    central nervous system

  •  
  • dDAVP

    deamino-8-D-arginine vasopressin

  •  
  • DI

    diabetes insipidus

  •  
  • NSAID

    nonsteroidal antiinflammatory drug

  •  
  • SIADH

    syndrome of inappropriate secretion of antidiuretic hormone

  •  
  • SUN

    serum urea nitrogen

  •  
  • V2 receptor

    vasopressin-2 receptor

1
Moritz
ML
,
Ayus
JC
.
Preventing neurological complications from dysnatremias in children
.
Pediatr Nephrol
.
2005
;
20
(
12
):
1687
1700
2
Zieg
J
.
Hyponatremia in children: from pathophysiology to therapy [in Czech]
.
Cas Lek Cesk
.
2016
;
155
(
3
):
35
40
3
Ályarez
LE
,
González
CE
.
Pathophysiology of sodium disorders in children [in Spanish]
.
Rev Chil Pediatr
.
2014
;
85
(
3
):
269
280
4
Janus
DM
,
Wojcik
M
,
Zygmunt-Górska
A
,
Wyrobek
L
,
Urbanik
A
,
Starzyk
JB
.
Adipsic diabetes insipidus in pediatric patients
.
Indian J Pediatr
.
2014
;
81
(
12
):
1307
1314
5
Di Iorgi
N
,
Napoli
F
,
Allegri
AEM
, et al
.
Diabetes insipidus–diagnosis and management
.
Horm Res Paediatr
.
2012
;
77
(
2
):
69
84
6
Kronenberg
H
,
Williams
RH
,
Melmed
S
,
Polonsky
KS
,
Larsen
PR
.
Williams Textbook of Endocrinology
.
Philadelphia, PA
:
Saunders/Elsevier
;
2008
7
Cheetham
T
,
Baylis
PH
.
Diabetes insipidus in children: pathophysiology, diagnosis and management
.
Paediatr Drugs
.
2002
;
4
(
12
):
785
796
8
Dabrowski
E
,
Kadakia
R
,
Zimmerman
D
.
Diabetes insipidus in infants and children
.
Best Pract Res Clin Endocrinol Metab
.
2016
;
30
(
2
):
317
328
9
King
LS
,
Agre
P
.
Pathophysiology of the aquaporin water channels
.
Annu Rev Physiol
.
1996
;
58
:
619
648
10
Fujiwara
TM
,
Bichet
DG
.
Molecular biology of hereditary diabetes insipidus
.
J Am Soc Nephrol
.
2005
;
16
(
10
):
2836
2846
11
Engel
A
,
Fujiyoshi
Y
,
Agre
P
.
The importance of aquaporin water channel protein structures
.
EMBO J
.
2000
;
19
(
5
):
800
806
12
Zieg
J
.
Evaluation and management of hyponatraemia in children
.
Acta Paediatr
.
2014
;
103
(
10
):
1027
1034
13
Thrasher
TN
,
Keil
LC
.
Regulation of drinking and vasopressin secretion: role of organum vasculosum laminae terminalis
.
Am J Physiol
.
1987
;
253
(
1 pt 2
):
R108
R120
14
Robertson
GL
,
Aycinena
P
,
Zerbe
RL
.
Neurogenic disorders of osmoregulation
.
Am J Med
.
1982
;
72
(
2
):
339
353
15
Baylis
PH
,
Cheetham
T
.
Diabetes insipidus
.
Arch Dis Child
.
1998
;
79
(
1
):
84
89
16
Baylis
PH
.
Osmoregulation and control of vasopressin secretion in healthy humans
.
Am J Physiol
.
1987
;
253
(
5, pt 2
):
R671
R678
17
Rowe
JW
,
Shelton
RL
,
Helderman
JH
,
Vestal
RE
,
Robertson
GL
.
Influence of the emetic reflex on vasopressin release in man
.
Kidney Int
.
1979
;
16
(
6
):
729
735
18
Saifan
C
,
Nasr
R
,
Mehta
S
, et al
.
Diabetes insipidus: a challenging diagnosis with new drug therapies
.
ISRN Nephrol
.
2013
;
2013
:
797620
19
Braverman
LE
,
Mancini
JP
,
McGoldrick
DM
.
Hereditary idiopathic diabetes insipidus. A case report with autopsy findings
.
Ann Intern Med
.
1965
;
63
:
503
508
20
Hagiwara
D
,
Arima
H
,
Morishita
Y
, et al
.
Arginine vasopressin neuronal loss results from autophagy-associated cell death in a mouse model for familial neurohypophysial diabetes insipidus
.
Cell Death Dis
.
2014
;
5
:
e1148
21
Tian
D
,
Cen
J
,
Nie
M
,
Gu
F
.
Identification of five novel arginine vasopressin gene mutations in patients with familial neurohypophyseal diabetes insipidus
.
Int J Mol Med
.
2016
;
38
(
4
):
1243
1249
22
Rutishauser
J
,
Spiess
M
,
Kopp
P
.
Genetic forms of neurohypophyseal diabetes insipidus
.
Best Pract Res Clin Endocrinol Metab
.
2016
;
30
(
2
):
249
262
23
Arima
H
,
Oiso
Y
.
Mechanisms underlying progressive polyuria in familial neurohypophysial diabetes insipidus
.
J Neuroendocrinol
.
2010
;
22
(
7
):
754
757
24
Pépin
L
,
Colin
E
,
Tessarech
M
, et al
.
A new case of PCSK1 pathogenic variant with congenital proprotein convertase 1/3 deficiency and literature review
.
J Clin Endocrinol Metab
.
2019
;
104
(
4
):
985
993
25
Boutzios
G
,
Livadas
S
,
Marinakis
E
,
Opie
N
,
Economou
F
,
Diamanti-Kandarakis
E
.
Endocrine and metabolic aspects of the Wolfram syndrome
.
Endocrine
.
2011
;
40
(
1
):
10
13
26
Amr
S
,
Heisey
C
,
Zhang
M
, et al
.
A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2
.
Am J Hum Genet
.
2007
;
81
(
4
):
673
683
27
McCabe
MJ
,
Alatzoglou
KS
,
Dattani
MT
.
Septo-optic dysplasia and other midline defects: the role of transcription factors: HESX1 and beyond
.
Best Pract Res Clin Endocrinol Metab
.
2011
;
25
(
1
):
115
124
28
Secco
A
,
Allegri
AEM
,
di Iorgi
N
, et al
.
Posterior pituitary (PP) evaluation in patients with anterior pituitary defect associated with ectopic PP and septo-optic dysplasia
.
Eur J Endocrinol
.
2011
;
165
(
3
):
411
420
29
Werny
D
,
Elfers
C
,
Perez
FA
,
Pihoker
C
,
Roth
CL
.
Pediatric central diabetes insipidus: brain malformations are common and few patients have idiopathic disease
.
J Clin Endocrinol Metab
.
2015
;
100
(
8
):
3074
3080
30
Maghnie
M
,
Cosi
G
,
Genovese
E
, et al
.
Central diabetes insipidus in children and young adults
.
N Engl J Med
.
2000
;
343
(
14
):
998
1007
31
Maghnie
M
,
Ghirardello
S
,
De Bellis
A
, et al
.
Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin-cell antibodies and markers of autoimmunity
.
Clin Endocrinol (Oxf)
.
2006
;
65
(
4
):
470
478
32
Pivonello
R
,
De Bellis
A
,
Faggiano
A
, et al
.
Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology
.
J Clin Endocrinol Metab
.
2003
;
88
(
4
):
1629
1636
33
Iwama
S
,
Sugimura
Y
,
Kiyota
A
, et al
.
Rabphilin-3A as a targeted autoantigen in lymphocytic infundibulo-neurohypophysitis
.
J Clin Endocrinol Metab
.
2015
;
100
(
7
):
E946
E954
34
Harano
Y
,
Honda
K
,
Akiyama
Y
,
Kotajima
L
,
Arioka
H
.
A case of IgG4-related hypophysitis presented with hypopituitarism and diabetes insipidus
.
Clin Med Insights Case Rep
.
2015
;
8
:
23
26
35
Makras
P
,
Alexandraki
KI
,
Chrousos
GP
,
Grossman
AB
,
Kaltsas
GA
.
Endocrine manifestations in Langerhans cell histiocytosis
.
Trends Endocrinol Metab
.
2007
;
18
(
6
):
252
257
36
Sakamoto
K
,
Morimoto
A
,
Shioda
Y
,
Imamura
T
,
Imashuku
S
;
Japan LCH Study Group (JLSG)
.
Central diabetes insipidus in pediatric patients with Langerhans cell histiocytosis: results from the JLSG-96/02 studies
.
Pediatr Blood Cancer
.
2019
;
66
(
1
):
e27454
37
Kruis
RWJ
,
Schouten-van Meeteren
AYN
,
Finken
MJJ
, et al
.
Management and consequences of postoperative fluctuations in plasma sodium concentration after pediatric brain tumor surgery in the sellar region: a national cohort analysis
.
Pituitary
.
2018
;
21
(
4
):
384
392
38
Yamada
S
,
Fukuhara
N
,
Yamaguchi-Okada
M
, et al
.
Therapeutic outcomes of transsphenoidal surgery in pediatric patients with craniopharyngiomas: a single-center study
.
J Neurosurg Pediatr
.
2018
;
21
(
6
):
549
562
39
Haddad
NG
,
Nabhan
ZM
,
Eugster
EA
.
Incidence of central diabetes insipidus in children presenting with polydipsia and polyuria
.
Endocr Pract
.
2016
;
22
(
12
):
1383
1386
40
Bockenhauer
D
,
van’t Hoff
W
,
Dattani
M
, et al
.
Secondary nephrogenic diabetes insipidus as a complication of inherited renal diseases
.
Nephron Physiol
.
2010
;
116
(
4
):
23
29
41
Sperling
MA
.
Pediatric Endocrinology E-Book
.
Amsterdam, Netherlands
:
Elsevier Health Sciences
;
2014
42
Djermane
A
,
Elmaleh
M
,
Simon
D
,
Poidvin
A
,
Carel
JC
,
Léger
J
.
Central diabetes insipidus in infancy with or without hypothalamic adipsic hypernatremia syndrome: early identification and outcome
.
J Clin Endocrinol Metab
.
2016
;
101
(
2
):
635
643
43
Fenske
W
,
Allolio
B
.
Clinical review: current state and future perspectives in the diagnosis of diabetes insipidus: a clinical review
.
J Clin Endocrinol Metab
.
2012
;
97
(
10
):
3426
3437
44
Elder
CJ
,
Dimitri
PJ
.
Diabetes insipidus and the use of desmopressin in hospitalised children
.
Arch Dis Child Educ Pract Ed
.
2017
;
102
(
2
):
100
104
45
Hiyama
TY
,
Utsunomiya
AN
,
Matsumoto
M
, et al
.
Adipsic hypernatremia without hypothalamic lesions accompanied by autoantibodies to subfornical organ
.
Brain Pathol
.
2017
;
27
(
3
):
323
331
46
Bourque
CW
.
Central mechanisms of osmosensation and systemic osmoregulation
.
Nat Rev Neurosci
.
2008
;
9
(
7
):
519
531
47
Moritz
ML
,
Ayus
JC
.
The changing pattern of hypernatremia in hospitalized children
.
Pediatrics
.
1999
;
104
(
3 pt 1
):
435
439
48
Fenske
W
,
Quinkler
M
,
Lorenz
D
, et al
.
Copeptin in the differential diagnosis of the polydipsia-polyuria syndrome–revisiting the direct and indirect water deprivation tests
.
J Clin Endocrinol Metab
.
2011
;
96
(
5
):
1506
1515
49
Christ-Crain
M
,
Bichet
DG
,
Fenske
WK
, et al
.
Diabetes insipidus
.
Nat Rev Dis Primers
.
2019
;
5
(
1
):
54
50
Fenske
W
,
Refardt
J
,
Chifu
I
, et al
.
A copeptin-based approach in the diagnosis of diabetes insipidus
.
N Engl J Med
.
2018
;
379
(
5
):
428
439
51
Hayashi
Y
,
Kita
D
,
Watanabe
T
, et al
.
Prediction of postoperative diabetes insipidus using morphological hyperintensity patterns in the pituitary stalk on magnetic resonance imaging after transsphenoidal surgery for sellar tumors
.
Pituitary
.
2016
;
19
(
6
):
552
559
52
Hayashi
Y
,
Aida
Y
,
Sasagawa
Y
, et al
.
Delayed occurrence of diabetes insipidus after transsphenoidal surgery with radiologic evaluation of the pituitary stalk on magnetic resonance imaging
.
World Neurosurg
.
2018
;
110
:
e1072
e1077
53
Czernichow
P
,
Garel
C
,
Léger
J
.
Thickened pituitary stalk on magnetic resonance imaging in children with central diabetes insipidus
.
Horm Res
.
2000
;
53
(
suppl 3
):
61
64
54
Christ-Crain
M
,
Fenske
WK
.
Copeptin in the differential diagnosis of hypotonic polyuria
.
J Endocrinol Invest
.
2020
;
43
(
1
):
21
30
55
Balanescu
S
,
Kopp
P
,
Gaskill
MB
,
Morgenthaler
NG
,
Schindler
C
,
Rutishauser
J
.
Correlation of plasma copeptin and vasopressin concentrations in hypo-, iso-, and hyperosmolar states
.
J Clin Endocrinol Metab
.
2011
;
96
(
4
):
1046
1052
56
Tuli
G
,
Tessaris
D
,
Einaudi
S
,
Matarazzo
P
,
De Sanctis
L
.
Copeptin role in polyuria-polydipsia syndrome differential diagnosis and reference range in paediatric age
.
Clin Endocrinol (Oxf)
.
2018
;
88
(
6
):
873
879
57
Du
JM
,
Sang
G
,
Jiang
CM
,
He
XJ
,
Han
Y
.
Relationship between plasma copeptin levels and complications of community-acquired pneumonia in preschool children
.
Peptides
.
2013
;
45
:
61
65
58
Morgenthaler
NG
,
Struck
J
,
Alonso
C
,
Bergmann
A
.
Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin
.
Clin Chem
.
2006
;
52
(
1
):
112
119
59
Burckhardt
MA
,
Wellmann
M
,
Fouzas
S
, et al
.
Sexual disparity of copeptin in healthy newborn infants
.
J Clin Endocrinol Metab
.
2014
;
99
(
9
):
E1750
E1753
60
Leung
AK
,
McArthur
RG
,
McMillan
DD
, et al
.
Circulating antidiuretic hormone during labour and in the newborn
.
Acta Paediatr Scand
.
1980
;
69
(
4
):
505
510
61
Rosen
CJ
,
Ingelfinger
JR
.
A reliable diagnostic test for hypotonic polyuria
.
N Engl J Med
.
2018
;
379
(
5
):
483
484
62
Rouatbi
H
,
Zigabe
S
,
Gkiougki
E
,
Vranken
L
,
Van Linthout
C
,
Seghaye
MC
.
Biomarkers of neonatal stress assessment: a prospective study
.
Early Hum Dev
.
2019
;
137
:
104826
63
Kelen
D
,
Andorka
C
,
Szabó
M
,
Alafuzoff
A
,
Kaila
K
,
Summanen
M
.
Serum copeptin and neuron specific enolase are markers of neonatal distress and long-term neurodevelopmental outcome
.
PLoS One
.
2017
;
12
(
9
):
e0184593
64
Summanen
M
,
Seikku
L
,
Rahkonen
P
, et al
.
Comparison of umbilical serum copeptin relative to erythropoietin and S100B as asphyxia biomarkers at birth
.
Neonatology
.
2017
;
112
(
1
):
60
66
65
Blohm
ME
,
Arndt
F
,
Sandig
J
, et al
.
Cardiovascular biomarkers in paired maternal and umbilical cord blood samples at term and near term delivery
.
Early Hum Dev
.
2016
;
94
:
7
12
66
Refardt
J
,
Winzeler
B
,
Christ-Crain
M
.
Copeptin and its role in the diagnosis of diabetes insipidus and the syndrome of inappropriate antidiuresis
.
Clin Endocrinol (Oxf)
.
2019
;
91
(
1
):
22
32
67
Vergier
J
,
Fromonot
J
,
Alvares De Azevedo Macedo
A
, et al
.
Rapid differential diagnosis of diabetes insipidus in a 7-month-old infant: the copeptin approach
.
Arch Pediatr
.
2018
;
25
(
1
):
45
47
68
Mishra
G
,
Chandrashekhar
SR
.
Management of diabetes insipidus in children
.
Indian J Endocrinol Metab
.
2011
;
15
(
suppl 3
):
S180
S187
69
Zheng
K
,
Xie
Y
,
Li
H
.
Congenital nephrogenic diabetes insipidus presented with bilateral hydronephrosis and urinary infection: a case report
.
Medicine (Baltimore)
.
2016
;
95
(
22
):
e3464
70
Karthikeyan
A
,
Abid
N
,
Sundaram
PCB
, et al
.
Clinical characteristics and management of cranial diabetes insipidus in infants
.
J Pediatr Endocrinol Metab
.
2013
;
26
(
11–12
):
1041
1046
71
Maghnie
M
,
Genovese
E
,
Lundin
S
,
Bonetti
F
,
Arico
M
.
Iatrogenic [corrected] extrapontine myelinolysis in central diabetes insipidus: are cyclosporine and 1-desamino-8-D-arginine vasopressin harmful in association? [published correction appears in J Clin Endocrinol Metab. 1997;82(7):2282]
.
J Clin Endocrinol Metab
.
1997
;
82
(
6
):
1749
1751
72
Rivkees
SA
,
Dunbar
N
,
Wilson
TA
.
The management of central diabetes insipidus in infancy: desmopressin, low renal solute load formula, thiazide diuretics
.
J Pediatr Endocrinol Metab
.
2007
;
20
(
4
):
459
469
73
Smego
AR
,
Backeljauw
P
,
Gutmark-Little
I
.
Buccally administered intranasal desmopressin acetate for the treatment of neurogenic diabetes insipidus in infancy
.
J Clin Endocrinol Metab
.
2016
;
101
(
5
):
2084
2088
74
Blanco
EJ
,
Lane
AH
,
Aijaz
N
,
Blumberg
D
,
Wilson
TA
.
Use of subcutaneous DDAVP in infants with central diabetes insipidus
.
J Pediatr Endocrinol Metab
.
2006
;
19
(
7
):
919
925
75
Abraham
MB
,
Rao
S
,
Price
G
,
Choong
CS
.
Efficacy of hydrochlorothiazide and low renal solute feed in neonatal central diabetes insipidus with transition to oral desmopressin in early infancy
.
Int J Pediatr Endocrinol
.
2014
;
2014
(
1
):
11
76
Al Nofal
A
,
Lteif
A
.
Thiazide diuretics in the management of young children with central diabetes insipidus
.
J Pediatr
.
2015
;
167
(
3
):
658
661
77
Chanson
P
,
Salenave
S
.
Treatment of neurogenic diabetes insipidus
.
Ann Endocrinol (Paris)
.
2011
;
72
(
6
):
496
499
78
Juul
KV
,
Van Herzeele
C
,
De Bruyne
P
,
Goble
S
,
Walle
JV
,
Nørgaard
JP
.
Desmopressin melt improves response and compliance compared with tablet in treatment of primary monosymptomatic nocturnal enuresis
.
Eur J Pediatr
.
2013
;
172
(
9
):
1235
1242
79
Marín
GR
,
Baspineiro
B
,
Vilca
I
.
Treatment with sublingual desmopressin in two infants with hydranencephaly and central diabetes insipidus [in Spanish]
.
Arch Argent Pediatr
.
2018
;
116
(
1
):
e93
e97
80
D’Alessandri-Silva
C
,
Carpenter
M
,
Ayoob
R
, et al
.
Diagnosis, treatment, and outcomes in children with congenital nephrogenic diabetes insipidus: a pediatric nephrology research consortium study
.
Front Pediatr
.
2020
;
7
:
550
81
Bouley
R
,
Hasler
U
,
Lu
HA
,
Nunes
P
,
Brown
D
.
Bypassing vasopressin receptor signaling pathways in nephrogenic diabetes insipidus
.
Semin Nephrol
.
2008
;
28
(
3
):
266
278
82
D’Alessandri-Silva
C
,
Carpenter
M
,
Mahan
JD
.
Treatment regimens by pediatric nephrologists in children with congenital nephrogenic diabetes insipidus: a MWPNC study
.
Clin Nephrol
.
2018
;
89
(
5
):
358
363
83
Assadi
F
,
Sharbaf
FG
.
Sildenafil for the treatment of congenital nephrogenic diabetes insipidus
.
Am J Nephrol
.
2015
;
42
(
1
):
65
69
84
Wattad
A
,
Chiang
ML
,
Hill
LL
.
Hyponatremia in hospitalized children
.
Clin Pediatr (Phila)
.
1992
;
31
(
3
):
153
157
85
Jones
DP
.
Syndrome of inappropriate secretion of antidiuretic hormone and hyponatremia
.
Pediatr Rev
.
2018
;
39
(
1
):
27
35
86
Seetharam
S
,
Thankamony
P
,
Gopakumar
KG
,
Krishna
KMJ
.
Higher incidence of syndrome of inappropriate antidiuretic hormone secretion during induction chemotherapy of acute lymphoblastic leukemia in indian children
.
Indian J Cancer
.
2019
;
56
(
4
):
320
324
87
Hasegawa
H
,
Okubo
S
,
Ikezumi
Y
, et al
.
Hyponatremia due to an excess of arginine vasopressin is common in children with febrile disease
.
Pediatr Nephrol
.
2009
;
24
(
3
):
507
511
88
Weitzman
RE
,
Kleeman
CR
.
The clinical physiology of water metabolism. Part III: the water depletion (hyperosmolar) and water excess (hyposmolar) syndromes
.
West J Med
.
1980
;
132
(
1
):
16
38
89
Manoogian
C
,
Pandian
M
,
Ehrlich
L
,
Fisher
D
,
Horton
R
.
Plasma atrial natriuretic hormone levels in patients with the syndrome of inappropriate antidiuretic hormone secretion
.
J Clin Endocrinol Metab
.
1988
;
67
(
3
):
571
575
90
Verbalis
JG
.
Whole-body volume regulation and escape from antidiuresis
.
Am J Med
.
2006
;
119
(
7,
suppl 1
):
S21
S29
91
Shepshelovich
D
,
Schechter
A
,
Calvarysky
B
,
Diker-Cohen
T
,
Rozen-Zvi
B
,
Gafter-Gvili
A
.
Medication-induced SIADH: distribution and characterization according to medication class
.
Br J Clin Pharmacol
.
2017
;
83
(
8
):
1801
1807
92
Janczar
S
,
Zalewska-Szewczyk
B
,
Mlynarski
W
.
Severe hyponatremia in a single-center series of 84 homogenously treated children with acute lymphoblastic leukemia
.
J Pediatr Hematol Oncol
.
2017
;
39
(
2
):
e54
e58
93
Salido
M
,
Macarron
P
,
Hernández-García
C
,
D’Cruz
DP
,
Khamashta
MA
,
Hughes
GRV
.
Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus
.
Lupus
.
2003
;
12
(
8
):
636
639
94
Holtmann
M
,
Krause
M
,
Opp
J
,
Tokarzewski
M
,
Korn-Merker
E
,
Boenigk
HE
.
Oxcarbazepine-induced hyponatremia and the regulation of serum sodium after replacing carbamazepine with oxcarbazepine in children
.
Neuropediatrics
.
2002
;
33
(
6
):
298
300
95
Ball
SG
.
Hyponatraemia
.
J R Coll Physicians Edinb
.
2010
;
40
(
3
):
240
245
96
Zerbe
R
,
Stropes
L
,
Robertson
G
.
Vasopressin function in the syndrome of inappropriate antidiuresis
.
Annu Rev Med
.
1980
;
31
:
315
327
97
Feldman
BJ
,
Rosenthal
SM
,
Vargas
GA
, et al
.
Nephrogenic syndrome of inappropriate antidiuresis
.
N Engl J Med
.
2005
;
352
(
18
):
1884
1890
98
Biebermann
H
,
Kleinau
G
,
Schnabel
D
, et al
.
A new multisystem disorder caused by the Gαs mutation p.F376V
.
J Clin Endocrinol Metab
.
2019
;
104
(
4
):
1079
1089
99
Moritz
ML
,
Ayus
JC
.
New aspects in the pathogenesis, prevention, and treatment of hyponatremic encephalopathy in children
.
Pediatr Nephrol
.
2010
;
25
(
7
):
1225
1238
100
Storey
C
,
Dauger
S
,
Deschenes
G
, et al
.
Hyponatremia in children under 100 days old: incidence and etiologies
.
Eur J Pediatr
.
2019
;
178
(
9
):
1353
1361
101
von Bismarck
P
,
Ankermann
T
,
Eggert
P
,
Claviez
A
,
Fritsch
MJ
,
Krause
MF
.
Diagnosis and management of cerebral salt wasting (CSW) in children: the role of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)
.
Childs Nerv Syst
.
2006
;
22
(
10
):
1275
1281
102
Zieg
J
.
Pathophysiology of hyponatremia in children
.
Front Pediatr
.
2017
;
5
:
213
103
Spasovski
G
,
Vanholder
R
,
Allolio
B
, et al.;
Hyponatraemia Guideline Development Group
.
Clinical practice guideline on diagnosis and treatment of hyponatraemia. [published correction appears in Nephrol Dial Transplant. 2014;40(6):914]
.
Nephrol Dial Transplant
.
2014
;
29
(
suppl 2
):
i1
i39
104
Moritz
ML
.
Syndrome of inappropriate antidiuresis
.
Pediatr Clin North Am
.
2019
;
66
(
1
):
209
226
105
Williams
CN
,
Riva-Cambrin
J
,
Bratton
SL
.
Etiology of postoperative hyponatremia following pediatric intracranial tumor surgery
.
J Neurosurg Pediatr
.
2016
;
17
(
3
):
303
309
106
Willemsen
RH
,
Delgado-Carballar
V
,
Elleri
D
, et al
.
Tolvaptan use during hyperhydration in paediatric intracranial lymphoma with SIADH
.
Endocrinol Diabetes Metab Case Rep
.
2016
;
2016
:
16
0066
107
Koksoy
AY
,
Kurtul
M
,
Ozsahin
AK
,
Cayci
FS
,
Tayfun
M
,
Bayrakci
US
.
Tolvaptan use to treat SIADH in a child
.
J Pediatr Pharmacol Ther
.
2018
;
23
(
6
):
494
498
108
Imbriano
LJ
,
Ilamathi
E
,
Ali
NM
,
Miyawaki
N
,
Maesaka
JK
.
Normal fractional urate excretion identifies hyponatremic patients with reset osmostat
.
J Nephrol
.
2012
;
25
(
5
):
833
838
109
Sterns
RH
,
Riggs
JE
,
Schochet
SS
 Jr.
.
Osmotic demyelination syndrome following correction of hyponatremia
.
N Engl J Med
.
1986
;
314
(
24
):
1535
1542
110
Burke
WT
,
Cote
DJ
,
Iuliano
SI
,
Zaidi
HA
,
Laws
ER
.
A practical method for prevention of readmission for symptomatic hyponatremia following transsphenoidal surgery
.
Pituitary
.
2018
;
21
(
1
):
25
31
111
Deaver
KE
,
Catel
CP
,
Lillehei
KO
,
Wierman
ME
,
Kerr
JM
.
Strategies to reduce readmissions for hyponatremia after transsphenoidal surgery for pituitary adenomas
.
Endocrine
.
2018
;
62
(
2
):
333
339
112
Segar
JL
.
Neonatal diuretic therapy: furosemide, thiazides, and spironolactone
.
Clin Perinatol
.
2012
;
39
(
1
):
209
220
113
Soupart
A
,
Coffernils
M
,
Couturier
B
,
Gankam-Kengne
F
,
Decaux
G
.
Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH
.
Clin J Am Soc Nephrol
.
2012
;
7
(
5
):
742
747
114
Robertson
GL
.
Vaptans for the treatment of hyponatremia
.
Nat Rev Endocrinol
.
2011
;
7
(
3
):
151
161
115
Marx-Berger
D
,
Milford
DV
,
Bandhakavi
M
, et al
.
Tolvaptan is successful in treating inappropriate antidiuretic hormone secretion in infants
.
Acta Paediatr
.
2016
;
105
(
7
):
e334
e337
116
Rianthavorn
P
,
Cain
JP
,
Turman
MA
.
Use of conivaptan to allow aggressive hydration to prevent tumor lysis syndrome in a pediatric patient with large-cell lymphoma and SIADH
.
Pediatr Nephrol
.
2008
;
23
(
8
):
1367
1370
117
Lindsay
RS
,
Seckl
JR
,
Padfield
PL
.
The triple-phase response–problems of water balance after pituitary surgery
.
Postgrad Med J
.
1995
;
71
(
837
):
439
441
118
Edate
S
,
Albanese
A
.
Management of electrolyte and fluid disorders after brain surgery for pituitary/suprasellar tumours
.
Horm Res Paediatr
.
2015
;
83
(
5
):
293
301
119
Finken
MJJ
,
Zwaveling-Soonawala
N
,
Walenkamp
MJE
,
Vulsma
T
,
van Trotsenburg
ASP
,
Rotteveel
J
.
Frequent occurrence of the triphasic response (diabetes insipidus/hyponatremia/diabetes insipidus) after surgery for craniopharyngioma in childhood
.
Horm Res Paediatr
.
2011
;
76
(
1
):
22
26
120
Gürbüz
F
,
Taştan
M
,
Turan
İ
,
Yüksel
B
.
Efficiency of single dose of tolvaptan treatment during the triphasic episode after surgery for craniopharyngioma
.
J Clin Res Pediatr Endocrinol
.
2019
;
11
(
2
):
202
206
121
Patti
G
,
Scianguetta
S
,
Roberti
D
, et al
.
Familial neurohypophyseal diabetes insipidus in 13 kindreds and 2 novel mutations in the vasopressin gene
.
Eur J Endocrinol
.
2019
;
181
(
3
):
233
244
122
Winzeler
B
,
Zweifel
C
,
Nigro
N
, et al
.
Postoperative copeptin concentration predicts diabetes insipidus after pituitary surgery
.
J Clin Endocrinol Metab
.
2015
;
100
(
6
):
2275
2282
123
van der Linde
AAA
,
van Herwaarden
AE
,
Oosting
JD
,
Claahsen-van der Grinten
HL
,
de Grouw
EPLM
. For Debate: Personalized Health Care: As Exemplified by Home Sodium Measurements in a Child with Central Diabetes Insipidus and Impaired Thirst Perception. In:
Pediatr Endocrinol Rev
, vol.
15
.
2018
:
276
279
124
Green
RP
,
Landt
M
.
Home sodium monitoring in patients with diabetes insipidus
.
J Pediatr
.
2002
;
141
(
5
):
618
624
125
Tian
W
,
Fu
Y
,
Garcia-Elias
A
, et al
.
A loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia
.
Proc Natl Acad Sci U S A
.
2009
;
106
(
33
):
14034
14039
126
Mehta
A
,
Hindmarsh
PC
,
Mehta
H
, et al
.
Congenital hypopituitarism: clinical, molecular and neuroradiological correlates
.
Clin Endocrinol (Oxf)
.
2009
;
71
(
3
):
376
382
127
Canepa-Anson
R
,
Williams
M
,
Marshall
J
,
Mitsuoka
T
,
Lightman
S
,
Sutton
R
.
Mechanism of polyuria and natriuresis in atrioventricular nodal tachycardia
.
Br Med J (Clin Res Ed)
.
1984
;
289
(
6449
):
866
868
128
Tharaux
PL
,
Hagège
I
,
Placier
S
, et al
.
Urinary endothelin-1 as a marker of renal damage in sickle cell disease
.
Nephrol Dial Transplant
.
2005
;
20
(
11
):
2408
2413
129
Gold
PW
,
Kaye
W
,
Robertson
GL
,
Ebert
M
.
Abnormalities in plasma and cerebrospinal-fluid arginine vasopressin in patients with anorexia nervosa
.
N Engl J Med
.
1983
;
308
(
19
):
1117
1123
130
Gungor
T
,
Kokanalý
MK
,
Oztürkkan
D
,
Tapisiz
OL
,
Mollamahmutoglu
L
.
A case of nephrogenic diabetes insipidus caused by partial bilateral ureteral obstruction due to advanced stage ovarian carcinoma
.
Arch Gynecol Obstet
.
2009
;
280
(
4
):
679
681
131
Bockenhauer
D
,
Bichet
DG
.
Inherited secondary nephrogenic diabetes insipidus: concentrating on humans
.
Am J Physiol Renal Physiol
.
2013
;
304
(
8
):
F1037
F1042
132
Girisgen
I
,
Avcı
E
,
Yüksel
S
.
Assessment of serum levels of copeptin and corticotropin-releasing factor in children with monosymptomatic and non-monosymptomatic nocturnal enuresis
.
J Pediatr Urol
.
2019
;
15
(
4
):
393
398
133
Nalbantoğlu
B
,
Yazıcı
CM
,
Nalbantoğlu
A
, et al
.
Copeptin as a novel biomarker in nocturnal enuresis
.
Urology
.
2013
;
82
(
5
):
1120
1123
134
Latronico
N
,
Castioni
CA
.
Copeptin in critical illness
.
Clin Chem Lab Med
.
2014
;
52
(
10
):
1391
1393
135
Abdel-Fattah
M
,
Meligy
B
,
El-Sayed
R
,
El-Naga
YA
.
Serum copeptin level as a predictor of outcome in pneumonia
.
Indian Pediatr
.
2015
;
52
(
9
):
807
808
136
Wrotek
A
,
Jackowska
T
,
Pawlik
K
.
Sodium and copeptin levels in children with community acquired pneumonia
.
Adv Exp Med Biol
.
2015
;
835
:
31
36
137
Lin
C
,
Wang
N
,
Shen
ZP
,
Zhao
ZY
.
Plasma copeptin concentration and outcome after pediatric traumatic brain injury
.
Peptides
.
2013
;
42
:
43
47
138
Mastropietro
CW
,
Mahan
M
,
Valentine
KM
, et al
.
Copeptin as a marker of relative arginine vasopressin deficiency after pediatric cardiac surgery
.
Intensive Care Med
.
2012
;
38
(
12
):
2047
2054
139
Rey
C
,
García-Cendón
C
,
Martínez-Camblor
P
, et al
.
High levels of atrial natriuretic peptide and copeptin and mortality risk [in Spanish]
.
An Pediatr (Barc)
.
2016
;
85
(
6
):
284
290
140
Schlapbach
LJ
,
Frey
S
,
Bigler
S
, et al
.
Copeptin concentration in cord blood in infants with early-onset sepsis, chorioamnionitis and perinatal asphyxia
.
BMC Pediatr
.
2011
;
11
:
38
141
Smith
J
,
Halse
KG
,
Damm
P
, et al
.
Copeptin and MR-proADM in umbilical cord plasma reflect perinatal stress in neonates born to mothers with diabetes and MR-proANP reflects maternal diabetes
.
Biomarkers Med
.
2013
;
7
(
1
):
139
146
142
Wellmann
S
,
Benzing
J
,
Cippà
G
, et al
.
High copeptin concentrations in umbilical cord blood after vaginal delivery and birth acidosis
.
J Clin Endocrinol Metab
.
2010
;
95
(
11
):
5091
5096
143
Benzing
J
,
Wellmann
S
,
Achini
F
, et al
.
Plasma copeptin in preterm infants: a highly sensitive marker of fetal and neonatal stress
.
J Clin Endocrinol Metab
.
2011
;
96
(
6
):
E982
E985
144
Yeşil
A
,
Kanawati
A
,
Helvacıoğlu
Ç
,
Kaya
C
,
Özgün
ÇG
,
Cengiz
H
.
Identification of patients at risk for preeclampsia with the use of uterine artery Doppler velocimetry and copeptin
.
J Matern Fetal Neonatal Med
.
2017
;
30
(
22
):
2763
2768
145
Yeung
EH
,
Liu
A
,
Mills
JL
, et al
.
Increased levels of copeptin before clinical diagnosis of preeclampsia. [published correction appears in Hypertension. 2016;68(1):e4]
.
Hypertension
.
2014
;
64
(
6
):
1362
1367
146
Timur
H
,
Tokmak
A
,
Taflan
S
, et al
.
Investigation of maternal and cord blood erythropoietin and copeptin levels in low-risk term deliveries complicated by meconium-stained amniotic fluid
.
J Matern Fetal Neonatal Med
.
2017
;
30
(
6
):
665
669
147
Schiel
R
,
Perenthaler
TJ
,
Steveling
A
,
Stein
G
.
Plasma copeptin in children and adolescents with type 1 diabetes mellitus in comparison to healthy controls
.
Diabetes Res Clin Pract
.
2016
;
118
:
156
161
148
Wiromrat
P
,
Bjornstad
P
,
Vinovskis
C
, et al
.
Elevated copeptin, arterial stiffness, and elevated albumin excretion in adolescents with type 1 diabetes
.
Pediatr Diabetes
.
2019
;
20
(
8
):
1110
1117
149
Rothermel
J
,
Kulle
A
,
Holterhus
PM
,
Toschke
C
,
Lass
N
,
Reinehr
T
.
Copeptin in obese children and adolescents: relationships to body mass index, cortisol and gender
.
Clin Endocrinol (Oxf)
.
2016
;
85
(
6
):
868
873
150
Wojsyk-Banaszak
I
,
Sobkowiak
P
,
Jończyk-Potoczna
K
, et al
.
Evaluation of copeptin during pulmonary exacerbation in cystic fibrosis
.
Mediators Inflamm
.
2019
;
2019
:
1939740
151
Tenderenda-Banasiuk
E
,
Wasilewska
A
,
Filonowicz
R
,
Jakubowska
U
,
Waszkiewicz-Stojda
M
.
Serum copeptin levels in adolescents with primary hypertension
.
Pediatr Nephrol
.
2014
;
29
(
3
):
423
429
152
Zhao
J
,
Du
S
,
Yang
J
, et al
.
Usefulness of plasma copeptin as a biomarker to predict the therapeutic effectiveness of metoprolol for postural tachycardia syndrome in children
.
Am J Cardiol
.
2014
;
114
(
4
):
601
605
153
Zhao
J
,
Tang
C
,
Jin
H
,
Du
J
.
Plasma copeptin and therapeutic effectiveness of midodrine hydrochloride on postural tachycardia syndrome in children
.
J Pediatr
.
2014
;
165
(
2
):
290
294.e1
154
Pechmann
A
,
Wellmann
S
,
Stoecklin
B
,
Krüger
M
,
Zieger
B
.
Increased von Willebrand factor parameters in children with febrile seizures
.
PLoS One
.
2019
;
14
(
1
):
e0210004
155
Stöcklin
B
,
Fouzas
S
,
Schillinger
P
, et al
.
Copeptin as a serum biomarker of febrile seizures
.
PLoS One
.
2015
;
10
(
4
):
e0124663
156
Coelho
R
,
Levandowski
ML
,
Mansur
RB
, et al
.
Serum copeptin in children exposed to maltreatment
.
Psychiatry Clin Neurosci
.
2016
;
70
(
10
):
434
441
157
Thomsen
CF
,
Dreier
R
,
Goharian
TS
, et al
.
Association of copeptin, a surrogate marker for arginine vasopressin secretion, with insulin resistance: influence of adolescence and psychological stress
.
Peptides
.
2019
;
115
:
8
14
158
Prandota
J
.
Clinical pharmacology of furosemide in children: a supplement
.
Am J Ther
.
2001
;
8
(
4
):
275
289
159
Huang
EA
,
Feldman
BJ
,
Schwartz
ID
,
Geller
DH
,
Rosenthal
SM
,
Gitelman
SE
.
Oral urea for the treatment of chronic syndrome of inappropriate antidiuresis in children
.
J Pediatr
.
2006
;
148
(
1
):
128
131
160
Sarafidis
P
,
Loutradis
C
,
Ferro
CJ
,
Ortiz
A
.
SGLT-2 inhibitors to treat hyponatremia associated with SIADH: a novel indication?
Am J Nephrol
.
2020
;
51
(
7
):
553
555

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.