Hypernatremia/diabetes insipidus

OVERVIEW: What every practitioner needs to know

Are you sure your patient has hypernatremia/diabetes insipidus? What are the typical findings for this disease?

Diabetes insipidus (DI) presents clinically as pathologic polyuria and polydipsia and if volume depletion is present, serum sodium is greater than145 mEq/L and serum osmolality is greater than 300 mOsm/kg. Infants often present with failure to thrive, irritability, and intermittent fever. DI can result from a variety of causes associated with vasopressin deficiency (central DI) or resistance (nephrogenic DI).

A careful history should focus on establishing daily fluid intake and urinary output, including an assessment for nocturia and enuresis. Signs of volume depletion can be marked in patients without the ability to compensate by increasing fluid intake. In contrast, volume status may be nearly normal in patients able to increase their fluid, intake albeit at great inconvenience.

Risk factors for acquired forms of central DI include conditions that impact the vasopressin-secreting neurons or their fiber tract, such as head injury (either accidental or surgical), neoplasms, and infiltrative, infectious, or autoimmune diseases. Risk factors for acquired nephrogenic DI include metabolic alterations such as hypercalcemia and hypokalemia, exposure to certain drugs, or conditions affecting renal concentrating ability.

Pathologic polyuria or polydipsia (>2 L/m2/d) warrants a detailed evaluation to establish the underlying cause.

What other disease/condition shares some of these symptoms?

Primary polydipsia


Postoperative fluid diuresis

What caused this disease to develop at this time?

Central DI (Vasopressin Deficiency)

Genetic mutations

Vasopressin gene (autosomal dominant), onset by age 5 years; defect in gene processing leads to cellular stress and death

DIDMOAD syndrome (also known as Wolfram syndrome) includes diabetes insipidus, diabetes mellitus, optic atrophy, and deafness; a defect in the WFS1 or CISD2 gene leads to impaired endoplasmic reticulum function and intracellular calcium homeostasis

Acquired causes (resulting in vasopressin deficiency or damage to vasopressin neurons)

  • Trauma (accidental or neurosurgical) (see section on "triple phase response" below)

  • Congenital defects in hypothalamus/pituitary gland (e.g., septo-optic dysplasia)

  • Tumors disrupting vasopressin neurons or fiber tract (e.g., germinoma, pinealoma)

  • Infiltration (e.g., histiocytosis X, lymphocytic or hematologic malignancy)

  • Autoimmune or nonspecific inflammation

  • Infections (e.g., bacterial meningitis, congenital cytomegalovirus)

  • Drugs inhibiting release (ethanol, phenytoin, halothane, α-adrenergic agents, opiate antagonists)

Nephrogenic DI (Vasopressin Resistance)

Genetic mutations

Vasopressin V2 receptor gene (congenital X-linked)

Loss of function mutations

Aquaporin-2 gene (congenital autosomal recessive)

Loss of function mutations

Aquaporin-2 gene (autosomal dominant)

Defect in gene processing leads to cellular stress and death

Acquired causes



Drugs (e.g., lithium, demeclocycline, foscarnet, clozapine, amphotericin, methicillin, rifampin)

Impaired renal concentrating ability

Urinary obstruction

Renal failure

Polycystic kidney disease

Sickle cell disease

Excess water intake

Decreased sodium intake

Decreased protein intake


If pathologic polyuria or polydipsia (>2 L/m2/d) is suspected, a laboratory evaluation should be performed. First-morning fasting specimens of blood and urine after the patient has undergone the longest period without drinking will often provide the most important information. First-morning specimens, especially in young children, can put patients at increased risk of dehydration and electrolyte imbalance (e.g., hypernatremia) if fluids are restricted excessively.

The laboratory evaluation should include the analysis of serum for osmolality, sodium, potassium, calcium, blood urea nitrogen, creatinine, and glucose and the simultaneous analysis of urine for osmolality, specific gravity, and glucose. In the near future, the ability to measure copeptin, a reliable vasopressin surrogate that is co-secreted with vasopressin, should facilitate the evaluation of patients with suspected vasopressin deficiency.

Diagnostic criteria for DI:

Serum osmolality greater than 300 mOsm/kg H2O with urine osmolality less than 300 mOsm/kg H2O (obtained randomly or after short period of water deprivation, e.g., overnight).

DI possible (consider water deprivation study):

Serum osmolality 270-300 mOsm/kg H2O with pathologic polyuria/polydipsia.

DI unlikely

Serum osmolality less than 270 mOsm/kg H2O or urine osmolality greater than 600 mOsm/kg H2O (obtained randomly or after water deprivation).

For patients with confirmed DI, a serum vasopressin level will help determine if it is of central (low) or nephrogenic (high) origin.

Patients with central DI may be at risk for deficiencies in other pituitary hormones, such as thyroid-stimulating hormone, adrenocorticotropic hormone, growth hormone, and luteinizing hormone–follicle-stimulating hormone and should be screened for these hormones in the appropriate clinical context.

Would imaging studies be helpful? If so, which ones?

Magnetic resonance imaging (MRI) of the hypothalamus and pituitary gland should be performed in central DI presenting in infancy (e.g., septo-optic dysplasia) or later to screen for large masses affecting the vasopressin-secreting hypothalamic nuclei or small tumors affecting the pituitary stalk (e.g., germinomas, pinealomas). In cases of idiopathic central DI, serial MRI should be performed to rule out slowly growing pituitary stalk tumors. In addition, measurement of the β-subunit of human chorionic gonadotropin should be obtained in cerebrospinal fluid (more sensitive than serum); it is often secreted by these tumors.

Confirming the diagnosis

The diagnosis of DI is often made when the simultaneous measurement of serum osmolality (>300 mOsm/kg H2O) and urine osmolality (<300 mOsm/kg H2O) reveal a concentrated serum and a dilute urine. The measurement of a vasopressin level (or a copeptin level) during this setting will confirm central DI (if low/undetectable) or nephrogenic DI (if high).

For patients with pathologic polyuria/polydipsia and equivocal laboratory findings (i.e., serum osmolality 270-300 mOsm/kg H2O), a carefully monitored water deprivation test should be considered, with serial measurement of vital signs, body weight, urine output, electrolyte levels, serum osmolality, and urine osmolality. If during the study the patient manifests laboratory values consistent with DI (serum osmolality >300 mOsm/kg H2O and urine osmolality <300 mOsm/kg H2O), a serum vasopressin level should be obtained to distinguish between central and nephrogenic DI, followed by administration of subcutaneous aqueous vasopressin. A sharp rise in the urine osmolality after subcutaneous vasopressin administration is highly suggestive of central DI. Note that a water deprivation study has potential risks and should be conducted under the supervision of an endocrinologist.


Treatment of Central DI

Fluid therapy

Acute therapy with normal saline may be necessary to restore volume status, followed by slow administration of hypotonic fluid to restore normal serum osmolality and electrolyte homeostasis. Note that noninfant patients with an intact thirst mechanism should be able to maintain euvolemia with serum osmolality and sodium in the high-normal range, albeit at great inconvenience, except in the rare instance when the hypothalamic thirst center has also been affected by the underlying process.

Aqueous vasopressin therapy

Treatment of central DI of acute onset in the hospital setting, especially after neurosurgery, is best managed with intravenous aqueous vasopressin (~1.5 mU/kg/h), which results in serum levels of ~10 pg/mL). This therapy must be associated with fluid restriction (1L/m2/d or about two thirds of maintenance) to avoid water intoxication and hyponatremia. Higher levels of vasopressin (>1000 pg/mL) must be avoided to prevent cutaneous necrosis, hypertension, rhabdomyolysis, and cardiac arrhythmias. Transitioning patients from intravenous to oral fluids as soon as possible can facilitate regulation of serum osmolality, assuming their thirst sensation is intact.

Vasopressin analog therapy

Long-term management of children and adults with central DI is best accomplished with the vasopressin analog DDAVP, which is available as a nasal spray (onset of action 5-10 minutes) or oral tablet (onset of action 15-30 minutes). The nasal preparation can be titrated through the use of a rhinal tube (10 µg/0.1 mL). The dose of oral DDAVP is 10 times higher than the intranasal dose in the range of 25-300 µg every 8-12 hours. The actual dose is determined empirically based on the desired length of action.

To avoid water intoxication while the patient is taking DDAVP, he/she must be advised to "drink to thirst" and not consume water in excess of 1 L/m2/d (two thirds of maintenance). Intravenous administration of hypotonic fluid should also be restricted to avoid hyponatremia. It is generally recommended that patients experience a brief period of urinary breakthrough each day, unless the patient has the concomitant loss of thirst sensation, which complicates management.

Treatment of infants with DDAVP is complicated by the large fluid requirement necessary to meet caloric needs. The diuretic chlorothiazide has been used in some infants because of its ability to increase urine osmolality, thus somewhat lowering the total oral intake required. The use of subcutaneous DDAVP, together with fluid restriction, has been shown to result in highly reproducible periods of anti-diuresis in this population. This strategy can be used in the first months of life during the overnight period, allowing the infant to take fluids ad libitum during the day. An initial subcutaneous dose of DDAVP of 0.002-0.1 µg/kg/dose is considered safe and generally leads to a final dose in the range of 0.02 µg QD-0.08 µg BID.

Treatment of Nephrogenic DI

Acquired causes

The treatment of acquired causes of nephrogenic DI should be focused on eliminating the underlying cause (e.g., drug, urinary obstruction, electrolyte disturbance).

Congenital causes resulting from genetic mutations

The treatment of these conditions is quite challenging, with the primary goal being optimization of caloric intake while minimizing the obligate solute load and subsequent urine output. Despite early intervention, growth failure and significant cognitive impairment are common.

Pharmacologic therapy with combinations of thiazide diuretics, amiloride, and indomethacin can help reduce urine volume in some patients. In addition, high-dose DDAVP has proved useful in some patients with nephrogenic DI, possibly those with partial loss of function mutations in the V2 receptor gene.

What are the adverse effects associated with each treatment option?

In hospitalized patients receiving DDAVP or vasopressin therapy who are not in control of their own fluid intake (and especially in those patients who lack an intact thirst mechanism) great care must be taken to avoid fluid overload. This is the most common cause of hyponatremia, which can precipitate seizures if the change in serum osmolality is acute.

What are the possible outcomes of this disease?

Causes of central DI resulting from genetic and acquired causes are generally permanent because of destruction of vasopressin-secreting neurons. Central DI resulting from medication administration can be transient, if resulting from a block in vasopressin release. In the case of central DI arising after neurosurgical manipulation in the region of the posterior pituitary (see section on "triple phase response" below), the degree to which permanent or partial central DI remains is directly related to the number of vasopressin-releasing neurons that survive.

Nephrogenic DI resulting from genetic and some acquired causes are generally permanent because of defects in vasopressin signaling or irreversible kidney damage. Cases of nephrogenic DI resulting from most acquired causes (e.g., hypercalcemia, hypokalemia, and medication) are generally reversible.

What causes this disease and how frequent is it?

See above.

How do these pathogens/genes/exposures cause the disease?

See above.

Other clinical manifestations that might help with diagnosis and management

Triple Phase Response

Accidental or neurosurgical injury to the hypothalamus or posterior pituitary is a common cause of central DI and classically results in three distinct phases:

Transient DI (12-48 hours): results from injury or local inflammation affecting vasopressin-secreting neuron function

SIADH (1-10 days): results from uncontrolled release of ADH from vasopressin-secreting neurons undergoing retrograde axonal cell death; the duration of this phase may be related to the extent of cell death

Permanent or partial DI: permanent DI arises if the number of vasopressin-secreting neurons lost exceeds approximately 90%.


Patients with DI from any cause are at increased risk of acute dehydration/hypernatremia and its consequences if appropriate access to fluids is limited.

Patients receiving antidiuretic therapy (e.g., DDAVP or vasopressin therapy) are at increased risk of fluid overload/hyponatremia and its consequences if fluid therapy exceeds the patient's maximal threshold.


See above.

What is the Evidence?

Maghnie, M, Cosi, G, Genovese, E. "Central diabetes insipidus in children and young adults". N Engl J Med. vol. 343. 2000. pp. 988-1007.

Majzoub, JA, Muglia, LJ, Srivatsa, A., Sperling, MA. "Disorders of the posterior pituitary". Pediatric endocrinology. Saunders. 2014.

Blanco, EJ, Lane, AH, Aijaz, N. "Use of subcutaneous DDAVP in infants with central diabetes insipidus". J Pediatr Endocrinol Metab. vol. 19. 2006. pp. 919-25.

Knoers, N, Monnens, LH.. "Nephrogenic diabetes insipidus: clinical symptoms, pathogenesis, genetics and treatment". Pediatr Nephrol. vol. 6. 1992. pp. 476-82.

Pogacar, PR, Mahnke, S, Rivkees, SA.. "Management of central diabetes insipidus in infancy with low renal solute load formula and chlorothiazide". Curr Opin Pediatr. vol. 12. 2000. pp. 405-11.


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