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Arginine Vasopressin Disorder (Diabetes Insipidus)

Editor: Jared M. Radbel Updated: 1/11/2024 2:48:42 AM


Arginine vasopressin disorder is a clinical syndrome characterized by the passage of abnormally large volumes of urine (diabetes) that is dilute (hypotonic) and devoid of dissolved solutes (ie, insipid). They belong to a group of inherited or acquired disorders of polyuria and polydipsia. This is associated with insufficient arginine vasopressin (AVP), antidiuretic hormone (ADH) secretion, or renal response to AVP, resulting in hypotonic polyuria and compensatory/underlying polydipsia.[1] The hallmarks of diabetes insipidus (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]


In 2022, the Endocrine Society, European Society of Endocrinology, Pituitary Society, Society for Endocrinology, European Society for Paediatric Endocrinology, Endocrine Society of Australia, Brazilian Endocrine Society, and Japanese Endocrine Society all proposed to change the name of this disorder from central DI to arginine vasopressin deficiency (AVP-D), and nephrogenic DI to arginine vasopressin resistance (AVP-R).[4][5]

There are multiple reasons to consider changing the name of diabetes insipidus currently. First and foremost, the usage of the term "diabetes" in both diabetes mellitus and diabetes insipidus has confused patients and their caregivers. Although the terms "mellitus" and "insipidus" differentiate between the clinical characteristics of these two distinct causes of polyuria, the common term "diabetes" has led to misunderstandings, mainly when non-endocrine specialists are treating patients with DI. Some healthcare professionals fail to recognize the difference between these two disorders, resulting in severe consequences such as withholding desmopressin treatment in central DI cases, leading to adverse outcomes and even deaths.[6]

In response to these unfortunate and preventable occurrences, national safety alerts have been issued, surveys among endocrinologists have been conducted, and a global task force comprising experienced clinicians involved in the care of DI patients has emerged. These collective efforts have created a strong motivation to change the condition's name.[4] Second, a recent survey published in The Lancet Diabetes & Endocrinology, which included over 1000 patients with central diabetes insipidus, revealed that 85% preferred a name change. The primary reason behind this preference was their encounters with healthcare professionals who exhibited an insufficient understanding of the disease, often confusing it with diabetes mellitus.[7] Notably, 87% of the surveyed patients believed that this lack of knowledge and resulting clinical confusion negatively affected the management of their condition, leading to unnecessary blood sugar measurements and the prescription of medications intended for diabetes mellitus during hospitalization.

Lastly, we believe medical disorder names should reflect the underlying pathophysiology. In the case of diabetes insipidus, the deficiency in the secretion and end-organ effects of the hormone arginine vasopressin (AVP) is now well-established. Therefore, for the reasons above, the working group proposes changing the name of DI to arginine vasopressin deficiency (AVP-D) for central causes and arginine vasopressin resistance (AVP-R) for nephrogenic reasons.[4] 


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1. Arginine Vasopressin Deficiency [AVP-D, formerly known as Central Diabetes Insipidus or CDI)]

Based on a literature review, idiopathic AVP-D is the most common cause of AVP-D.[8][9] In a report of 79 participants, AVP-D was idiopathic in 52% of cases. Other cases were from a tumor or infiltrative disease in 38% of cases.[9]

a) Idiopathic AVP-D

Approximately 30% to 50% of cases of AVP-D are idiopathic. These are suggested to be associated with an autoimmune etiology in most patients.[10][11][12] 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 (through an MRI pituitary gland sequence) reveals thickening or enlargement of these structures. A longitudinal study demonstrated the presence of cytoplasmic antibodies directed against vasopressin cells in patients with endocrine abnormalities.[11]

Another study of 150 patients with AVP-D evaluated their association with other autoimmune diseases and their correlation with imaging findings. The study reported the etiology of AVP-D was idiopathic in 43%, familial in 4%, granulomatous in 8%, and an acquired cause like cranial trauma, tumor, or surgery in 45% of cases.[12] 

Antibodies to vasopressin cells were found in approximately one-third of the patients with idiopathic disease and about one-quarter with non-idiopathic disease.[12] Antibody positivity was independently associated with those aged younger 30 at disease onset, a history of autoimmune disease, or pituitary stalk thickening. Autoimmune AVP-D was highly probable in young patients with a history of autoimmune disease and pituitary stalk thickening.

The autoantigens involved in idiopathic AVP-D are not entirely elucidated. In patients with lymphocytic infundibuloneurohypophysitis (LINH), autoantibodies to rabphilin-3A, a regulator of secretory vesicle trafficking, are found in most patients.[13] Other autoimmune conditions associated with AVP-D include Immunoglobulin G4-related systemic syndrome, granulomatosis with polyangiitis (PGA), and autoimmune polyglandular syndrome type I.[14] 

b) Familial and Congenital Disease 

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

  • Familial AVP-D, also called familial neurohypophyseal DI or FNDI, is an autosomal dominant disease caused by mutations in the gene encoding antidiuretic hormone (eg, ADH/AVP).[15] 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.[16]
  • Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is characterized by AVP-D, diabetes mellitus, optic atrophy, and deafness, with cognitive and psychiatric issues that may appear later in life [17]; it is inherited as an autosomal recessive trait with incomplete penetrance and involves defects in the endoplasmic reticulum. Prognosis is poor with death at a mean age of 30 years.[18][18]
  • Proprotein convertase subtilisin/kexin-type 1 (PCSK1) gene deficiency—The PCSK1 gene encodes a 753-amino acid precursor, preproPC1/3, which is processed into active PC1/3.[19] PC1/3 is involved in processing numerous digestive and hypothalamic prohormones, including AVP. A deficiency of ADH leads to AVP-D.
  • Congenital hypopituitarism — AVP-D has been described in patients with congenital hypopituitarism with or without ectopia of the posterior pituitary lobe.[20][21] The defects in posterior pituitary function in these disorders include symptomatic AVP-D, nocturia, reduced ADH release after osmotic challenge, and hypodipsia or polydipsia.
  • Septo-optic dysplasia—A very rare congenital disorder based on the presence of two or more of the following: optic nerve hypoplasia, pituitary hormone abnormalities and midline brain defects. 

c) Neurosurgery or Trauma 

Traumatic injury to the hypothalamus and posterior pituitary or neurosurgery with a transsphenoidal approach usually induces AVP-D.[22][23][24] The incidence of AVP-D in such instances varies with the extent of injury (10-20% for surgical removal of adenomas limited to the sella to 60%-80% after removal of large tumors). Minimally invasive endoscopic pituitary surgery has seen a lower incidence of AVP-D than the traditional approach.[25] Craniopharyngioma is associated with AVP-D both before and particularly after surgery.[26] 

Despite the relatively high frequency of AVP-D in patients undergoing neurosurgery, most cases of polyuria in this setting are not due to AVP-D.[27] 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 AVP-D by measuring the urine osmolality, the response to water restriction, and ADH administration.

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 AVP-D.[8] AVP-D may also be observed in myelodysplastic syndrome

e) Adipsic DI

Adipsic DI develops when the same lesion causing AVP-D also affects hypothalamic osmoreceptors and has a high mortality. Adipsic DI is classically associated with craniopharyngioma and can also present with CNS trauma, tumors, or neurosurgical or neurovascular procedures.[28]  Moderate to severe hypernatremia develops when these thirst centers are impaired or cannot be expressed. This leads to 'adipsic DI.'[29] In such situations, dehydration may be the predominant symptom of AVP-D. The serum sodium concentration in untreated AVP-D is often in the high normal range, secondary to lack of stimulation of thirst centers in the brain to replace urinary water losses.[30]

f) Hypoxic encephalopathy

Hypoxic encephalopathy or severe ischemia (as seen with cardiopulmonary arrest or shock) can lead to diminished ADH release.[31] The severity of this defect varies, ranging from mild and asymptomatic to marked polyuria.

g) Infiltrative disorders 

Infiltrative disorders like Langerhans cell histiocytosis, granulomatosis with polyangiitis, autoimmune lymphocytic hypophysitis, and sarcoidosis are associated with AVP-D.[32][33][34][35][36]

2. Arginine Vasopressin Resistance (AVP-R, formerly known as Nephrogenic Diabetes Insipidus or NDI)

AVP-R refers to a decrease in the urinary concentrating ability of the kidney that results from resistance to the action of antidiuretic hormone (AVP/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 AVP-R are hereditary nephrogenic DI in children; while in adults, chronic lithium ingestion, and hypercalcemia predominate. Acquired causes are often partially reversible with cessation of the offending drug or correction of hypercalcemia.

a) Hereditary forms of AVP-R: Hereditary AVP-R is an uncommon disorder resulting in variable degrees of resistance to ADH.[37][38] 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% 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).[39]

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.[38][40] 

d) Lithium toxicity: About 20% 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).[41] Lithium inhibits the signaling pathway at cytotoxic concentrations, leading to aquaporin-2 water channel dysfunction.[41]

e) Hypercalcemia: A plasma calcium concentration persistently above 11 mg/dl (2.75 mmol/L) can impair renal concentrating ability.[42] 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.[42] 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.[43]

g) Other: AVP-R has been described in numerous other conditions. 

  • Kidney disorders: Symptomatic AVP-R can be seen in sickle cell disease or trait, autosomal dominant polycystic kidney disease and medullary cystic kidney disease, renal amyloidosis, and Sjögren syndrome.[44][45][55]
  • Drugs: Aside from lithium, various medications like cidofovir, foscarnet, amphotericin B, ofloxacin, ifosfamide, and orlistat have been shown to cause NDI. Drug-induced AVP-R is typically reversible, at least in part.

3. Pregnancy-Induced/Gestational form of Arginine Vasopressin disorder (gAVP-d)

  • Increased vasopressin metabolism is induced by placental cysteine aminopeptidase.[46][47] This is usually compensated for by increased fluid intake.

4. Primary Polydipsia[48]

a) Psychogenic polydipsia: This is very common in those with psychiatric disorders, particularly chronic schizophrenia, but also patients with other psychiatric disorders. It is thought to be related to anterior hippocampal stress reaction and is present in 11% to 20% of patients with chronic schizophrenia. Please see our companion StatPearls article "Primary Polydypsia."[49]

b) Drug-induced: Anticholinergics, and certain medications including phenothiazines, antipsychotics and high doses of nicotine induce a sense of "dry mouth," which can lead to increased water intake. 

c) Intracranial etiology: Hypothalamic tumors, tuberculous meningitis, sarcoidosis. In addition to causing AVP-D, these pathologies can affect thirst receptors causing increased water intake. They can also cause polyphagia as well. 

d) Dipsogenic DI: This condition is associated with the lowering of the hypothalamic threshold for thirst. Patients with this condition also often have hypothalamic, hippocampal neurodevelopmental, or psychiatric disorders. They are prone to becoming total body water overloaded and have very low AVP levels.[50]


Arginine vasopressin disorder (AVP-D) is an uncommon endocrine disorder affecting nearly 1 in 25,000 people, or about 0.004% of the global population.[51] On epidemiological review, DI does not show a preference for males or females.[52] It may develop at any age, with hereditary forms presenting earlier in life. Given the rare occurrence of this condition, the different forms can be missed in medical practice with poor consequences.[52]


Arginine vasopressin disorder (AVP-D), based on the site of pathology, can be caused by two different defects, ie, central and peripheral (nephrogenic) types.

AVP-D is secondary to inadequate or impaired secretion of 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 many 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 AVP-D, it is much more common not to have AVP-D 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 AVP-D 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 destroy the anterior and posterior pituitary.

AVP-D 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, AVP's release site shifts superiorly to the pituitary stalk and median eminence. The development of AVP-D 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 (eg, metastatic lesions, acute hemorrhage), or granulomatous disease, with more diffuse hypothalamic involvement (eg, sarcoidosis, histiocytosis).

A second general principle is that the neurohypophysis's capacity to synthesize AVP greatly exceeds 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 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 destroy the AVP magnocellular neuron cell bodies must have a significant degree of destruction to make AVP-d.

The serum concentration in untreated AVP-D is often in the high normal range, secondary to stimulation of thirst centers in the brain to replace urinary water losses.[30] Moderate to severe hypernatremia develops when these thirst centers are impaired or cannot be expressed. This leads to 'adipsic DI.'[29] 

In AVP-R, the site of action of AVP at the levels of kidneys is at defective V2 receptors.[53] 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); a G protein couples them 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.[54][53][55] Mutations of the AVPR2 receptor cause more than 90% of cases of congenital AVP-R.[38][56]

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 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 AVP-D are fairly drastic. The osmoregulation negative feedback loop responds to changes in serum osmolality, with normal serum osmolality between 285 mOsm/kg and 295 mOsm/kg. When osmolality is greater than 295 mOsm/kg, a loss of body water occurs, leading to concentrated blood. 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 AVP synthesis and release from the posterior pituitary gland. Even slight differences, such as a 5% to 10% decrease in blood volume or a 5% decrease in mean arterial pressure, can stimulate ADH release. In general, the body first regulates AVP secretion in response to osmoregulation. In severe volume depletion, baroreceptor stimulation of AVP takes precedence over osmoregulation.[57]

Gestational Form of Arginine Vasopressin Disorder  (gAVP-D)

Gestational AVP-D occurs in about 1 in 30,000 pregnancies due to the degradation of AVP by the enzyme cysteine aminopeptidase secreted by the fetus. Vasopressinase levels are typically higher in pregnant women (up to 300 times higher), more so in twin pregnancies.[42][43] However, hormone levels are often normal, suggesting pregnancy may unmask a subtle underlying deficiency of AVP. Gestational AVP-D typically presents in the third trimester and spontaneously resolves about 2 or 3 weeks postpartum.[43] It is often underdiagnosed, since polyuria during pregnancy is considered normal and does not generally cause complications.[44]

History and Physical

The primary symptoms common to both AVP-D and AVP-R 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.[58] Urine is usually most concentrated in the morning due to a lack of fluid ingestion overnight and increased AVP 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 nonspecific and can be secondary to other factors.[59]

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.[59] 

Patients with AVP-D may develop decreased bone mineral density at the lumbar spine and femoral neck. The mechanism for this is unclear.[60] Additional symptoms in patients with AVP-D may include weakness, lethargy, fatigue, and myalgias.


Diagnosing the type of AVP-D is essential for making optimal treatment decisions. A potential misdiagnosis and the resultant treatment can cause catastrophic consequences.[1] For instance, severe hyponatremia can occur if primary polydipsia is misdiagnosed as AVP-D and desmopressin treatment is initiated.[61]

The various polyuria-polydipsia syndromes often show overlapping features. This makes the diagnosis and classification of AVP-d difficult. The water deprivation test or the indirect water deprivation test generally helps distinguish between different forms of this disease. This interpretation is complicated in partial AVP-D, AVP-R, or chronic primary polydipsia. Typically, patients with partial AVP-D or AVP-R retain some amount of response to water deprivation and desmopressin administration.[62][44] 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 AVP-R.[62]

An algorithmic approach can help diagnose and classify suspected cases of AVP-D.[58] It involves the following steps: 1. Confirmation of hypotonic polyuria 2. Diagnosis of the type of polyuria-polydipsia syndrome 3.Identification of the underlying etiology.[30] 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 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.[45][63][64][65] 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 suggests causes besides DI. 

Polyuria is defined as the excretion of a urinary volume >150 mL/kg/24 hours at birth, >100 to 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 is to establish the presence of polyuria. Once polyuria is confirmed and other causes are ruled out, urine osmolality is measured. Hypotonic urine is typically defined as <300 mOsm/kg osmolality in the setting of high or normal sodium.

If the urine osmolality is >800 mOsm/kg, this indicates optimal plasma AVP levels and appropriate renal response to AVP, thereby ruling out any AVP-D.[1] In many 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 individuals with a urine osmolality of ≥300 mOsm/kg and <800 mOsm/kg, a 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 AVP-D or AVP-R, while a low normal or low sodium (<135 mmol/L) could indicate primary polydipsia as the underlying disorder.[64][65]

Similarly, a high plasma osmolality (≥300 mOsm/Kg) is typically seen in AVP-D, while a normal or low plasma osmolality (≤280 mOsm/Kg) is usually seen in primary polydipsia.[45][63] 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 and 1.030. It helps distinguish the co-existent conditions like DM and AVP-D.[66]

2. Diagnosis of the type of polyuria-polydipsia syndrome  

To differentiate AVP-D and AVP-R and primary polydipsia, perform a water deprivation test and desmopressin (DDAVP) trial. Typically a 7-hour deprivation test is adequate to diagnose DI. Primary polydipsia may require more extended 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 AVP-D or AVP-R, 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 is higher than 295 to 300 mOsm/kg
  • Plasma Na greater than 145 mEq

If AVP-R 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 mOsm/kg to 300 mOsm/kg
  • Plasma sodium greater than 145 meq/L
  • Loss of 5% of body weight or signs of volume depletion

Once the diagnosis of AVP is established, desmopressin administration can distinguish between AVP-D and AVP-R. 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% in complete central DI and up to 50% in partial central DI.

In cases of AVP-R, water deprivation suboptimally increases urine osmolality. DDAVP minimally increases urine osmolality in partial AVP-R, with no increase in complete AVP-R.

AVP-D 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.[67][68] AVP measurement is laborious, and the average turn-around time for measuring AVP is 3 to 7 days.[62][69] 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.[8][53] Unlike plasma AVP measurement, copeptin measurement in the plasma is relatively less cumbersome. It has several advantages: copeptin can remain stable for days after blood sampling and can be measured relatively quickly.[53] 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.[27][54] Moreover, plasma copeptin demonstrates the same response to plasma osmolality and volume changes as plasma AVP.[9][27] 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.[8][9][11][38][27]

Hypertonic saline infusion test: 

  • Hypertonic saline (3% saline, 1027 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 the disorder

Once the type of polyuria-polydipsia syndrome is identified, efforts must be undertaken to diagnose the underlying pathology. In conditions of AVP-D, 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.[70] 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).

In most cases, AVP-R is acquired, usually in the setting of certain drugs like lithium, demeclocycline.[30] Therefore, it is important to review the patient's medication list. Initial laboratory investigations help identify electrolyte abnormalities such as hypercalcemia and hypokalemia.[30][71] 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 AVP-R, and prompt evaluation for these disorders is necessary.[1][30] Congenital causes for AVP-R include mutations in the gene for the aquaporin-2 receptor (autosomal recessive) and V2 receptor (X-linked recessive inheritance). They must be suspected of childhood-onset AVP-R.[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.[72] 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 10 mcg by nasal insufflation or 4 mcg subcutaneously or intravenously. In newborns or young infants, the amount is one mcg subcutaneously or intravenously over 20 minutes with a maximum dose of 0.4 mcg/kg.[73](B3)

It is essential to replete fluid losses in all DI, as some patients may have thirst impairment and will not respond adequately to water intake.[74][75][76] Thirst is essential so that the excess urinary water losses can be replaced. Patients without an intact thirst mechanism can develop severe hypernatremia.(B3)

1. Arginine Vasopressin Deficiency (AVP-D, formerly known as Central Diabetes Insipidus or CDI)

The preferred therapy is DDAVP.[73] Typically, treatment is maintained for AVP-D, which varies depending on the cause. The minimum dose should be administered to control polyuria adequately.(B3)

It is crucial 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 AVP-D include a low-solute diet (low salt, low protein), thiazide diuretics, chlorpropamide, carbamazepine, and non-steroidal anti-inflammatory drugs (NSAID).[77][78][79] DDAVP is considered safe during pregnancy.(B3)

2. Arginine Vasopressin Resistance (AVP-R, formerly known as Nephrogenic Diabetes Insipidus or NDI)

The first step is to correct the underlying cause. If possible, discontinue the offending agent, such as lithium.[80](A1)

A low-solute diet may decrease urine output. The lower amount of total solutes ingested, the lower the urine volume that will be excreted.[81]

Thiazide diuretics may be used in conjunction with dietary changes. The mechanism of administering a polyuria diuretic promotes 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.[82]

Other treatment options include DDAVP and NSAIDs. NSAIDs inhibit prostaglandin synthesis, which has antagonistic effects on ADH.[80](A1)

Differential Diagnosis

Differentials of polyuria include:

  • Primary polydipsia 
  • Glucosuria in uncontrolled diabetes mellitus 
  • Urea diuresis after a high-protein diet
  • Polyuria is also seen after administering large volumes of intravenous dextrose or other IV fluids. 
  • Tissue catabolism results in urea production leading to polyuria
  • Use of mannitol
  • Irritable bladder syndrome

Nocturia can also be secondary to:

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


Prognosis for patients with AVP-D often depends on the underlying pathology, such as brain tumors, metastatic disease, sarcoidosis, infiltrative disease, or other pathology. Patients with genetic syndromes such as Wolfram Syndrome and septo-optic dysplasia have especially poor prognosis.[83] 

The prognosis for most patients with AVP-R is excellent if the underlying primary cause can be treated. Lithium discontinuation can restore normal kidney function, but the AVP-R may be permanent in some patients. Patients with g-AVP-D usually have a good prognosis, so long as hydration is encouraged. 

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


Without medical treatment, the potential DI 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. 

Deterrence and Patient Education

Patients play a crucial role in their care. They should be educated on the following points:

  • Medication compliance is critical - this is especially true with any diuretic medications or if DDAVP is prescribed
  • Reduce salt and protein intake to decrease polyuria
  • Maintain fluid intake, even to the extreme of carrying water at all times
  • Monitor for signs of dehydration (eg, dizziness, light-headedness, confusion, inability to think clearly)

Enhancing Healthcare Team Outcomes

There are many causes of DI, and the condition 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 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 and osmolality of the urine should be monitored before administering desmopressin. Also, regular monitoring of electrolytes should be considered.



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Level 1 (high-level) evidence


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