Diabetes Insipidus

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Continuing Education Activity

Diabetes insipidus (DI) is a disease process that results in either decreased release of antidiuretic hormone (ADH, also known as vasopressin or AVP) or decreased response to ADH, causing electrolyte imbalances. There are two types of diabetes insipidus, central and nephrogenic, and each has congenital and acquired causes. This activity reviews the etiology, presentation, evaluation, and management of diabetes insipidus and the role of the interprofessional team in evaluating, diagnosing, and managing this condition.


  • Review the pathophysiology of the two primary categories of diabetes insipidus causes in each category.
  • Outline the factors in evaluating a patient with suspected diabetes insipidus, including laboratory analysis.
  • Describe the treatment options for diabetes insipidus, depending on the specific etiology.
  • Explain the importance of improving coordination among the interprofessional team to enhance care for patients affected by diabetes insipidus.


Diabetes insipidus (DI) is a clinical syndrome characterized by the passage of abnormally large volumes of urine (diabetes) that is dilute (hypotonic) and devoid of taste from dissolved solutes (i.e., insipid). They belong to a group of inherited or acquired disorders of polyuria and polydipsia. This is associated with insufficient arginine vasopressin (AVP) or antidiuretic hormone (ADH) secretion or renal response to AVP, resulting in hypotonic polyuria and compensatory/underlying polydipsia.[1] The hallmarks of DI include polyuria (> 50 mL/kg), dilute urine (osmolality < 300 mOsm/L), and increased thirst with the intake of up to 20 L/day fluid intake.[2] Untreated DI can cause hypovolemia, dehydration, and electrolyte imbalances.[3]


Diabetes insipidus is caused by a problem with vasopressin production in the pituitary gland (central) or the action of vasopressin in the kidneys (nephrogenic). Based on the site of its pathology, it can be divided into central diabetes insipidus (CDI) and nephrogenic diabetes insipidus (NDI). 

1. Central Diabetes Insipidus (CDI)

Based on a literature review, the most common cause of Central diabetes insipidus (CDI) is idiopathic diabetes insipidus (DI).[4][5] In a report of 79 participants, CDI was idiopathic in 52 percent of cases. Other cases were from a tumor or infiltrative disease in 38 percent of cases.[5]

a) Idiopathic CDI 

Approximately 30 to 50 percent of cases of CDI are idiopathic. They are suggested to be associated with an autoimmune etiology in most patients.[6][7][8][7] The autoimmune process is characterized by lymphocytic inflammation of the pituitary gland, specifically the pituitary stalk and the posterior pituitary gland. Early in its course, imaging of the gland (MRI pituitary gland sequence) reveals thickening or enlargement of these structures. A longitudinal study demonstrated the presence of cytoplasmic antibodies directed against vasopressin cells (Ab-positive) in patients with endocrine abnormalities.[7] Another study of 150 patients with CDI evaluated their association with other autoimmune diseases and their correlation with imaging findings. The study reported etiology of CDI was idiopathic in 43 percent, familial in 4 percent, granulomatous in 8 percent, and an acquired cause like cranial trauma, tumor, or surgery in 45 percent of cases.[8] Antibodies to vasopressin cells were found in approximately one-third of the patients with idiopathic disease and about one-quarter with non-idiopathic disease.[8] Antibody positivity was independently associated with age less than 30 years at disease onset in those with the idiopathic illness, a history of autoimmune disease, or pituitary stalk thickening. Autoimmune CDI was highly probable in young patients with autoimmune disease and pituitary stalk thickening history.

The autoantigens involved in idiopathic CDI are not entirely elucidated. In patients with lymphocytic infundibuloneurohypophysitis (LINH), autoantibodies to rabphilin-3A, a regulator of secretory vesicle trafficking, are found in a large majority of patients.[9] Other autoimmune conditions associated with CDI include Immunoglobulin (Ig) G4-related systemic syndrome, granulomatosis with polyangiitis (PGA), and autoimmune polyglandular syndrome type I.[10] 

b) Familial and congenital disease 

Many familial and congenital diseases have been associated with CDI. These include familial CDI, Wolfram syndrome, proprotein convertase subtilisin/kexin type 1 (PCSK1) gene deficiency, and congenital diseases such as congenital hypopituitarism and septo-optic dysplasia. 

  • Familial CDI also called familial neurohypophyseal DI or FNDI, is an autosomal dominant disease caused by mutations in the gene encoding antidiuretic hormone (ADH; also called arginine vasopressin or AVP).[11] ADH and its corresponding carrier, neurophysin II, are synthesized as a composite precursor by the magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus.[12]
  • Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is characterized by CDI, diabetes mellitus, optic atrophy, and deafness, with cognitive and psychiatric issues that may appear later in life [13]; it is inherited as an autosomal recessive trait with incomplete penetrance.
  • Proprotein convertase subtilisin/kexin-type 1 (PCSK1) gene deficiency — The PCSK1 gene encodes a 753-amino acid precursor, preproPC1/3, which is processed in the ER into its proenzyme form, proPC1/3. ProPC1/3 is then modified by cleavage of its prodomain into active PC1/3 [14]. PC1/3 is involved in processing numerous digestive and hypothalamic prohormones, including ADH. A deficiency of ADH leads to CDI.
  • Congenital hypopituitarism — CDI has been described in patients with congenital hypopituitarism with or without ectopia of the posterior pituitary lobe.[15][16] The defects in posterior pituitary function in these disorders include symptomatic CDI, nocturia, reduced ADH release after osmotic challenge, and hypodipsia or polydipsia.

c) Neurosurgery or trauma 

Traumatic injury to the hypothalamus and posterior pituitary or neurosurgery with a transsphenoidal approach usually induces DI.[17][18][19][18] The incidence of CDI in such instances varies with the extent of injury (10-20 percent for surgical removal of adenoma limited to the sella to 60-80 percent after removal of large tumors). Minimally invasive endoscopic pituitary surgery has seen a lower incidence of CDI than the traditional approach.[20] Craniopharyngioma is associated with CDI both before and particularly after surgery.[21] 

Despite the relatively high frequency of CDI in patients undergoing neurosurgery, most cases of polyuria in this setting are not due to CDI.[22] More common causes are the excretion of excess fluid administered during surgery and an osmotic diuresis induced by mannitol or glucocorticoids (which cause hyperglycemia and glucosuria) to reduce cerebral edema. These conditions are generally differentiated from CDI by measuring the urine osmolality and the response to water restriction and the administration of ADH.

d) Cancer

Primary or secondary (most often due to lung cancer, leukemia, or lymphoma) tumors in the brain can involve the hypothalamic-pituitary region and lead to CDI.[4] CDI may also be observed in myelodysplastic syndrome

e) Hypoxic encephalopathy

Hypoxic encephalopathy or severe ischemia (as seen with cardiopulmonary arrest or shock) can lead to diminished ADH release.[23] The severity of this defect varies, ranging from mild and asymptomatic to marked polyuria.

f) Infiltrative disorders 

Infiltrative disorders like Langerhan's cell histiocytosis[24][25], granulomatosis with polyangitis[26], autoimmune lymphocytic hypophysitis[27], and sarcoidosis[28] are associated with CDI.  

2. Nephrogenic Diabetes Insipidus (NDI)

Nephrogenic diabetes insipidus (DI) refers to a decrease in the urinary concentrating ability of the kidney that results from resistance to the action of antidiuretic hormone (ADH). The pathology can be due to resistance at the ADH site of activity in the collecting tubules or interference with the countercurrent mechanism due, for example, to medullary injury or decreased sodium chloride reabsorption in the medullary aspect of the thick ascending limb of the loop of Henle.

The most common causes of NDI are hereditary nephrogenic DI in children, chronic lithium ingestion, and hypercalcemia in adults. Acquired causes are often partially reversible with cessation of the offending drug or correction of hypercalcemia.

a) Hereditary nephrogenic DI — Hereditary nephrogenic DI is an uncommon disorder resulting in variable degrees of resistance to ADH.[29][30] There are two different receptors for ADH: the V1 (AVPR1) and V2 (AVPR2) receptors. The AVPR2 gene is located on the X chromosome (Xq-28).

b) Vasopressin V2 receptor gene mutations — Approximately 90 percent of cases of hereditary nephrogenic DI have X-linked inheritance. They are due to mutations in the AVPR2 gene, which encodes for a dysfunctional vasopressin V2 receptor (V2R).[31]

c) Aquaporin-2 gene mutation — The second form of hereditary nephrogenic DI is caused by a defect in the aquaporin-2 gene that encodes the ADH-sensitive water channels in the collecting tubule cells. This variant may have autosomal recessive or autosomal dominant modes of inheritance.[30][32] 

d) Lithium toxicity - About 20 percent of patients on chronic lithium therapy develop polyuria causing NDI. The adverse effect of lithium is mediated by the entry into the principal cells in the collecting tubule via the epithelial sodium channel (ENaC).[33] Lithium inhibits the signaling pathway at cytotoxic concentrations, leading to dysfunction of the aquaporin-2 water channel.[33]

e) Hypercalcemia - A plasma calcium concentration persistently above 11 mg/dl (2.75 mmol/L) can impair renal concentrating ability.[34] The mechanisms with which these occur are not entirely understood. This defect may be associated with reductions in sodium chloride reabsorption in the thick ascending loop of Henle, thereby interfering with the countercurrent mechanism and ADH's ability to increase collecting tubule water permeability.[34] The concentrating defect induced by hypercalcemia is generally reversible with a normal serum calcium concentration restoration. However, the defect may persist in patients with permanent medullary damage. 

f) Hypokalemia - Persistent severe hypokalemia can impair urinary concentrating ability. The mechanisms by which this occurs are incompletely understood. Downregulation of urea transporters may also contribute to the impairment of urinary concentrating ability induced by potassium depletion.[35]

g) Other: NDI has been described in numerous other conditions. 

  • Kidney disorders: Symptomatic nephrogenic DI can be seen in sickle cell disease or trait, autosomal dominant polycystic kidney disease and medullary cystic kidney disease [53,54], renal amyloidosis [55], and Sjögren's syndrome
  • Drugs: Other than lithium, various other drugs like cidofovir, foscarnet, amphotericin B, ofloxacin, ifosfamide, and orlistat have been shown to cause NDI. Drug-induced nephrogenic DI is typically reversible, at least in part.
  • Pregnancy: A transient form is noted in a few patients during the second half of their pregnancy.[36]

3. Pregnancy-Induced/Gestational Diabetes Insipidus

  • Increased vasopressin metabolism induced by placental cysteine aminopeptidase.[37]

4. Primary Polydipsia

a) Psychogenic polydipsia 

b) Drug-induced: Anticholinergics, phenothiazines 

c) Intracranial etiology: Hypothalamic tumors, tuberculous meningitis, sarcoidosis

d) Lowering of the hypothalamic threshold for thirst - Dipsogenic DI 


Diabetes insipidus is an uncommon endocrine disorder affecting nearly 1 in 25,000 people, or about 0.004% of the global population.[38] On epidemiological review, DI does not show a predilection for males or females.[39] It may develop at any age, with hereditary forms developing earlier in life.  Given the rare occurrence of this condition, the different forms can be missed in medical practice. Untreated DI negatively impacts the quality of life of the patient.[39]


Diabetes insipidus, based on the site of pathology, can be caused by two different defects, i.e., central and peripheral (Nephrogenic) types.

The central DI is secondary to Inadequate/ impaired secretion of Vasopressin (AVP) from the posterior pituitary gland in response to osmotic stimulation and a decrease in blood pressure. AVP is synthesized as a precursor complex in the supraoptic and periventricular nuclei of the hypothalamus and encoded by the AVP-neurophysin II gene. It is released by calcium-dependent exocytosis. The osmoreceptors are found in the hypothalamus, arterial baroreceptors, and the atrial stretch receptors. In most cases, the neurohypophysis is destroyed by various acquired or congenital anatomic lesions secondary to pressure or infiltration. The resulting hypotonic diuresis depends on the degree of destruction of the neurohypophysis, leading to complete or partial deficiency of AVP secretion.

Despite the wide variety of lesions that can potentially cause CDI, it is much more common not to have CDI in the presence of such lesions than to produce the syndrome. This apparent inconsistency can be understood by considering several common neurohypophyseal physiology principles and pathophysiology relevant to all these causes. Lesions contained within the sella turcica that destroy only the posterior pituitary generally do not cause CDI because the cell bodies of the magnocellular neurons that synthesize AVP remain intact, and the site of release of AVP shifts more superiorly, typically into the blood vessels of the median eminence at the base of the brain. Perhaps the best examples of this phenomenon are large pituitary macroadenomas that completely destroy the anterior and posterior pituitary. DI is a distinctly unusual presentation for such pituitary adenomas because the destruction of the posterior pituitary by such slowly enlarging intrasellar lesions merely destroys the nerve terminals, but not the cell bodies, of the AVP neurons. As this occurs, the site of release of AVP shifts more superiorly to the pituitary stalk and median eminence. The development of DI from a pituitary adenoma is so uncommon, even with macroadenomas that completely obliterate sellar contents sufficiently to cause panhypopituitarism, that its presence should lead to consideration of alternative diagnoses, such as craniopharyngioma. This often causes damage to the median eminence because of adherence of the capsule to the base of the hypothalamus, more rapidly enlarging sellar or suprasellar masses that do not allow sufficient time for shifting the site of AVP release more superiorly (e.g., metastatic lesions, acute hemorrhage), or granulomatous disease, with more diffuse hypothalamic involvement (e.g., sarcoidosis, histiocytosis).

A second general principle is that the capacity of the neurohypophysis to synthesize AVP is greatly in excess of the body's daily needs for maintaining water homeostasis. Carefully controlled studies of the surgical section of the pituitary stalk in dogs have demonstrated that the destruction of 80% to 90% of the magnocellular neurons in the hypothalamus is required to produce polyuria and polydipsia in these species. Thus, even lesions that cause destruction of the AVP magnocellular neuron cell bodies must produce a large degree of destruction to produce DI.

As the name suggests, in Nephrogenic DI, the site of action of AVP at the levels of kidneys is the V2 receptors are defective.[40] These V2 receptors are found in the basolateral membrane of principal cells in the late distal tubule and the whole length of the collecting duct (CD); they are coupled by a G protein to cyclic adenosine monophosphate generation, which ultimately leads to the insertion of aquaporin-porin (AQP2) water channels into the apical membrane of this otherwise water-impermeable segment.[41][40][42] More than 90% of cases of congenital NDI are caused by mutations of the AVP V  receptor.[43][30] Various mutations cause several different defects in cellular processing and function of the receptor but can be classified into four general categories based on differences in transport to the cell surface and AVP binding and/or stimulation of adenylyl cyclase, as follows: (1) the mutant receptor is not inserted in the membrane; (2) the mutant receptor is inserted in the membrane but does not bind or respond to AVP; (3) the mutant receptor is inserted in the membrane and binds AVP but does not activate adenylyl cyclase; or (4) the mutant protein is inserted into the membrane and binds AVP but responds subnormally in terms of adenylyl cyclase activation. 

The two principle negative feedback loops associated with body water homeostasis and the effects of DI are quite drastic. The osmoregulation negative feedback loop responds to changes in serum osmolality, with normal serum osmolality being between 285 mOsm/kg and 295 mOsm/kg. When osmolality is greater than 295 mOsm/kg, a loss of body water occurs, and the blood is more concentrated. The baroregulation negative feedback loop responds to changes in blood volume and blood pressure. The hypothalamus responds to the baroreceptor changes by suppressing or increasing ADH synthesis and release from the posterior pituitary gland. Even slight changes, such as a 5-10% decrease in blood volume or a 5% decrease in mean arterial pressure, can stimulate ADH release. In general, the body first regulates ADH secretion in response to osmoregulation. In severe volume depletion, baroreceptor stimulation of ADH takes precedence over osmoregulation.[44]

Gestational Diabetes Insipidus 

Gestational DI occurs in about 1 in 30,000 pregnancies[42] due to the degradation of AVP by the enzyme cysteine aminopeptidase. Vasopressinase levels are typically higher in pregnant women (up to 300 times higher), more so in twin pregnancies.[43] However, hormone levels are often normal, suggesting pregnancy unmasks a subtle underlying deficiency of AVP. Gestational DI typically presents in the third trimester[43] and spontaneously resolves about 2–3 weeks postpartum, but a diagnosis to reveal any underlying pathology is necessary. It is usually underdiagnosed since polyuria during pregnancy is considered normal and does not cause complications.[44]

History and Physical

The primary symptoms common to both types include polydipsia, polyuria, and nocturia. Polyuria is defined as a urine output of more than 3 L/day in adults or 2 L/m2 in children.[45] The urine is normally most concentrated in the morning due to a lack of fluid ingestion overnight and increased vasopressin secretion during the late sleep period. As a result, the first manifestation of a mild to moderate loss of concentrating ability is often nocturia. However, nocturia is often non-specific and can be secondary to other factors.[46]

In children, symptoms can be nonspecific, and they may present with severe dehydration, constipation, vomiting, fevers, irritability, failure to thrive, and growth retardation. In patients with central nervous system (CNS) tumors, headaches and visual defects may present in addition to the classic symptoms.[46]

The serum concentration in untreated CDI is often in the high normal range, secondary to stimulation of thirst centers in the brain to replace urinary water losses.[47] Moderate to severe hyponatremia develops when these thirst centers are impaired or cannot be expressed. This leads to 'adipsic DI'.[48] Adipsic DI is classically associated with craniopharyngioma and can also present with CNS trauma, tumors, or neurosurgical or neurovascular procedures.[49] Furthermore, hypothalamic lesions cause alteration in the thirst mechanism. In such situations, dehydration may be the predominant symptom of DI. 

Patients with CDI may develop decreased bone mineral density at the lumbar spine and femoral neck. The mechanism for this is unclear. [50]

Additional symptoms in patients with diabetes insipidus may include weakness, lethargy, fatigue, and myalgias.


Diagnosing the type of DI is essential for making the optimal treatment decision. A potential misdiagnosis and the resultant treatment can cause catastrophic consequences.[1] For instance, if primary polydipsia is misdiagnosed as central DI and desmopressin treatment is initiated, severe hyponatremia can occur.[51]

The various polyuria-polydipsia syndromes often show overlapping features. This makes the diagnosis and classification of DI difficult. The water deprivation test or the indirect water deprivation test generally helps distinguish between different forms of DI. This interpretation is complicated in partial central DI, nephrogenic DI, or chronic primary polydipsia. Typically, patients with partial central or nephrogenic DI retain some amount of response to water deprivation and desmopressin administration.[52][53][52] In the case of chronic primary polydipsia, long-standing water diuresis blunts the renal medullary concentration gradient and causes down-regulation of the aquaporin-2 channels in the proximal tubule and the collecting duct due to suppressed endogenous AVP, thus creating a state mimicking nephrogenic DI.[52]

An algorithmic approach can help diagnose and classify suspected cases of DI.[45] It involves the following steps: 1. Confirmation of hypotonic polyuria 2. Diagnosis of the type of polyuria-polydipsia syndrome, and 3.Identification of the underlying etiology.[47] Performing diagnostic testing in this order can potentially aid with establishing the appropriate diagnosis and choosing the most relevant biochemical and imaging tests.

1. Confirmation of hypotonic polyuria 

The primary objective in this step involves differentiating between conditions that give rise to polyuria resulting from osmotic diuresis (such as in hyperglycemia) and DI/primary polydipsia, in which polyuria predominantly involves water diuresis.

The first step is to confirm if the patient indeed has polyuria. Calculate the total 24-hour urine volume to confirm polyuria. Obtain baseline values of plasma electrolytes, random serum, and urine osmolality.[54][55][56][57]. Ruling out other causes of polyuria is essential in this step. A 24-hour urine output of less than 2.5 L is reassuring and rules out osmoregulatory disruption. 

Polyuria is defined as the excretion of a urinary volume >150 ml/Kg/24 hours at birth, >100-110 ml/Kg/24 hours up to the age of 2 years, and >50 ml/Kg/24 hours in older children or adults. Patients need not hold any medications that can cause polyuria, such as diuretics or sodium-glucose co-transporter-2 (SGLT-2) inhibitors, for this step, as the goal of this step is to establish the presence of polyuria.   Once polyuria is confirmed, and other causes are ruled out, we measure the urine osmolality.    Hypotonic urine is typically defined as an osmolality of <300 mOsm/Kg.   If the urine osmolality is >800 mOsm/Kg, this indicates optimal plasma AVP levels and appropriate renal response to AVP, thereby ruling out any DI.[1] In most cases, polyuria with isotonic/hypertonic urine is driven by glucose, sodium, urea, or medications such as diuretics or mannitol.   In individuals with established hypotonic polyuria or in individuals with a urine osmolality of ≥300 mOsm/Kg and <800 mOsm/Kg, the further evaluation must be undertaken through laboratory investigations. Serum sodium and plasma osmolality measurements could assist with indicating the type of underlying polyuric state. A high serum sodium (>146 mmol/L) could point towards central or nephrogenic DI, while a low normal or low sodium (<135 mmol/L) could indicate primary polydipsia as the underlying disorder.[56][57] Similarly, a high plasma osmolality (≥300 mOsm/Kg) is typically seen in DI, while a normal or low plasma osmolality (≤280 mOsm/Kg) is usually seen in primary polydipsia.[54][55]   As an alternative to urine osmolality, urine-specific gravity is also useful in identifying a hypotonic polyuric disorder. For normal plasma osmolality, the urine specific gravity is between 1.003 to 1.030. It helps distinguish the co-existent conditions like DM and DI.[58]    

2. Diagnosis of the type of polyuria-polydipsia syndrome  

 To differentiate central and nephrogenic diabetes insipidus and primary polydipsia, perform a water deprivation test and desmopressin (DDAVP) trial. Typically a 7-hour deprivation test is adequate to diagnose diabetes insipidus. Primary polydipsia may require longer dehydration periods. The basic principle behind the water deprivation test is that in individuals with normal posterior pituitary and renal function (or those with primary polydipsia), an increase in plasma osmolality from dehydration stimulates AVP release from the posterior pituitary, which then leads to water reabsorption in the nephrons, thus resulting in concentration of urine and an increase in urine osmolality. In central or nephrogenic DI, the urine fails to concentrate optimally with water deprivation, and there is persistent excretion of hypotonic urine. 

In adults, the water restriction test should be discontinued when one of the following is reached:

  • Urine osmolality reaches the normal reference range.
  • Urine osmolality is stable on two to three consecutive hourly measurements, even with rising plasma osmolality.
  • Plasma osmolality greater than 295 mosmol/kg to 300 mosmol/kg
  • Plasma Na greater than 145 mEq

If nephrogenic diabetes insipidus is suspected in newborns and young infants, the diagnostic test of choice is DDAVP (1 mcg subcutaneously or intravenously over 20 minutes, maximum dose of 0.4 mcg/kg).

In children, the water deprivation test should be closely monitored. If one of the following endpoints is reached, discontinue the trial:

  • Urine osmolality reaches the normal reference range.
  • Plasma osmolality greater than 295 mosmol/kg to 300 mosmol/kg
  • Plasma sodium greater than 145 meq/L
  • Loss of 5% of body weight or signs of volume depletion

Once the diagnosis of DI is established, desmopressin administration can distinguish between central and nephrogenic DI. In central DI, once the deficient action of AVP is substituted with desmopressin administration, the urine osmolality should increase, while in nephrogenic DI, as the desmopressin is ineffective due to lack of renal response to its actions, the low urine osmolality persists.

The water deprivation trial is most accurate when DDAVP is not given. After water deprivation, studies have demonstrated that desmopressin can increase urine osmolality by greater than 100% incomplete central diabetes insipidus and up to 50% in partial central diabetes insipidus.

In cases of nephrogenic diabetes insipidus, water deprivation suboptimally increases urine osmolality. DDAVP minimally increases urine osmolality in partial nephrogenic diabetes insipidus, with no increase in urine osmolality in complete nephrogenic diabetes insipidus.

Central diabetes insipidus is diagnosed when there is evidence of plasma hyperosmolality (greater than 300 mosm/l), urine hyperosmolality (less than 300 mosm/l or urine/plasma osmolality less than 1), polyuria (urinary volume greater than 4 mL/kg/hr to 5 mL/kg/hr for two consecutive hours after surgery).

Limitations of measuring plasma AVP levels include rapid clearance with wide fluctuations due to the instability of AVP in plasma.[59][60][59] AVP measurement is laborious, and the average turn-around time for measuring AVP is 3-7 days.[52][61] [52]A related peptide of AVP, copeptin, is now emerging as a new, more stable marker to diagnose the various hypotonic polyuric states. 

Measurement of plasma copeptin 

Copeptin (Carboxy-Terminal-Pro-vasopressin) is the C-terminal peptide of pro-vasopressin co-secreted with AVP from the posterior pituitary (4,40). Unlike plasma AVP measurement, copeptin measurement in the plasma is relatively less cumbersome and has several advantages: copeptin can remain stable for days after blood sampling and can be measured relatively quickly (40). Plasma levels of copeptin strongly correlate with plasma AVP levels over a wide range of osmolalities, both in healthy individuals and those with DI or primary polydipsia (22,41). Moreover, plasma copeptin demonstrates the same response to plasma osmolality and volume changes as plasma AVP (5,22). Several studies have been conducted to validate the utility of plasma copeptin in diagnosing hypotonic polyuric states and to distinguish one form from the other (4,5,7,22,30).

Hypertonic saline infusion test 

Hypertonic saline (3% saline, 513 mOsm/L) infusion coupled with plasma copeptin measurement is an alternative test that is now being recommended by many experts in the field of DI as the preferred test to be used in place of the water deprivation test.

3. Identification of the cause of DI

Once the type of polyuria-polydipsia syndrome is identified, efforts must be undertaken to diagnose the underlying pathology. In conditions of central DI, a detailed clinical history with an exam should be performed to check for hormonal deficiencies. Biochemical tests should be conducted as per protocol following clinical evaluation.[62] An MRI of the sella and suprasellar regions with gadolinium needs to be obtained to evaluate for any anatomical disruptions of the pituitary or hypothalamic anatomy (macroadenomas, empty sella, infiltrative diseases).

Nephrogenic DI, in the majority of cases, is acquired, usually in the setting of certain drugs like lithium, demeclocycline, and others.[47] Therefore, it is important to review the patient's medication intake. Initial laboratory investigations help identify electrolyte abnormalities such as hypercalcemia and hypokalemia.[47][63] Any underlying acute or chronic renal disease (vascular, inflammatory, or neoplastic processes, polycystic kidney disease), obstructive uropathy, and systemic diseases such as amyloidosis or sickle cell disease can also give rise to nephrogenic DI, and prompt evaluation for these disorders is necessary.[47][1][47] Congenital causes for nephrogenic DI include mutations in the gene for the aquaporin-2 receptor (autosomal recessive) and the gene for the V-2 receptor (X-linked recessive inheritance) and must be suspected in childhood-onset nephrogenic DI.[1]

Primary polydipsia or dipsogenic DI is likely secondary to mood disorders or schizophrenia treatment. Various hypothalamic diseases like sarcoidosis, tuberculosis, trauma, and neoplasms alter the thirst response by lowering the thirst threshold, causing polydipsia. The anticholinergic nature of these drugs also leads to dry mouth and excessive water intake. 

Gestational diabetes insipidus occurs due to the enzymatic breakdown of the endogenous AVP by a placental cysteine aminopeptidase.[64] The workup for other etiologies must be considered when appropriate. 

Treatment / Management

DDAVP, an ADH analog, can be administered orally, intranasally, subcutaneously, or intravenously. In adults, the dose is ten mcg by nasal insufflation or 4mcg subcutaneously or intravenously. In newborns or young infants, the dose is one mcg subcutaneously or intravenously over 20 minutes with a maximum dose of 0.4 mcg/kg.[65]

It is essential to replete fluid losses in diabetes insipidus, as some patients may have thirst impairment and will not respond adequately to water intake.[66][67][68] Thirst is essential so that the excess urinary water losses can be replaced. Patients without an intact thirst mechanism can develop severe hypernatremia.

Central Diabetes Insipidus

The preferred therapy is DDAVP.[65] Typically, therapy is maintained for central diabetes insipidus, which varies depending on the cause. The minimum dose should be administered to control polyuria adequately.

It is important to monitor hyponatremia, as water retention can lead to sodium concentration changes that may cause brain injury. The patients and families should be educated to observe for nausea, vomiting, lethargy, headaches, confusion, seizures, and coma symptoms.

Other treatment options for central diabetes insipidus include a low-solute diet (low salt, low protein), thiazide diuretics, chlorpropamide, carbamazepine, and non-steroidal anti-inflammatory drugs (NSAID).[69][70][71]

DDAVP is considered safe during pregnancy.

Nephrogenic Diabetes Insipidus

The first step is to correct the underlying cause. If possible, discontinue the offending agent, such as lithium.[72]

A low-solute diet may decrease urine output. The lower amount of total solutes ingested, the lower the urine volume that will be excreted.[73]

Thiazide diuretics may be used in conjunction with dietary changes. The mechanism of administering a diuretic for polyuria is to promote the reduction of urine volume, which triggers the endogenous release of aldosterone. By having less water delivered distally, there would be less water loss in the collecting tubule, where ADH targets its effects.[74]

Other treatment options include DDAVP and NSAIDs. NSAIDs inhibit prostaglandin synthesis, which has antagonistic effects on ADH.[72]

Differential Diagnosis

Polyuria other than DI include

  • Primary polydipsia 
  • Glucosuria in uncontrolled diabetes mellitus 
  • Urea after a high-protein diet
  • Polyuria is also seen after administering large volumes of intravenous dextrose in water. 
  • Tissue catabolism results in urea production leading to polyuria
  • Use of Mannitol

Nocturia can be secondary to 

  • Drinking water or fluids before going to bed 
  • Prostatic hypertrophy in men 
  • Diabetes mellitus 


The prognosis for most patients with DI is excellent as long as the underlying primary cause can be treated. Lithium discontinuation can restore normal kidney function, but the nephrogenic DI may be permanent in some patients. 

As long as the individual has access to water, mortality can be avoided. However, the condition can lead to cardiovascular collapse, fever, and hypernatremia in children and older patients.


Without medical treatment, the potential diabetes insipidus complications include:

  • Chronic dehydration
  • Tachycardia
  • Decreased temperature
  • Hypotension
  • Weight loss
  • Fatigue
  • Headaches
  • Kidney damage
  • Brain damage


An endocrinology consult is often warranted to identify the etiology of hypernatremia secondary to central or nephrogenic causes. A neurosurgeon is involved in cases of pituitary tumors or craniopharyngioma. 

Pearls and Other Issues

Patients with significant electrolyte abnormalities should be closely monitored and admitted to the hospital.

Enhancing Healthcare Team Outcomes

There are many causes of DI, and the disorder is best managed by an interprofessional team that includes the primary care provider, nurse practitioner/physician assistant, internist, and pharmacist. Patient education is crucial. The key is to hydrate, replace the electrolytes, and then manage the primary condition causing DI. The pharmacist should keep track of all medications that can cause DI and make the appropriate recommendations to the clinician. The nurse should educate the patient on traveling to hot destinations because dehydration can exacerbate the symptoms. If possible, travel should be avoided until the condition is treated. In post-operative patients, the specific gravity of the urine and osmolality should be monitored before administering desmopressin. Also, regular monitoring of electrolytes should be considered.


The outlook for patients with DI depends on the cause. The prognosis for benign causes is good, but the prognosis is guarded if the cause is a malignancy.[75][41] With an interprofessional team approach, outcomes can improve. [Level 5]

Article Details

Article Author

Channing Hui

Article Author

Myra Khan

Article Author

Mahammed Z. Khan Suheb

Article Editor:

Jared M. Radbel


11/19/2022 3:42:09 PM



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