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Arginine Vasopressin Disorder (Diabetes Insipidus)

Authors

Channing Hui; Myra Khan1; Mahammed Z. Khan Suheb2; Jared M. Radbel3.

Affiliations
1 University of Michigan
2 University of Wisconsin
3 Rutgers Robert Wood Johnson

Last Update: January 11, 2024.

Continuing Education Activity

Arginine vasopressin disorder, formerly known as diabetes insipidus (DI), is a disease process that
results in either decreased release of antidiuretic hormone (ADH, also known as vasopressin or
AVP) or reduced response to ADH, causing electrolyte imbalances. There are two types of arginine
vasopressin disorder, namely arginine vasopressin deficiency, AVP-D, (formerly known as central
DI) and arginine vasopressin resistance, AVP-R (formerly known as nephrogenic DI), and each has
congenital and acquired causes. Arginine vasopressin disorder is caused by a problem with
vasopressin production in the pituitary gland (deficiency) or the action of vasopressin in the
kidneys (resistance). Based on the site of its pathology, it can be divided into Arginine vasopressin
deficiency (AVP-D) and Arginine vasopressin resistance (AVP-R). 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.

Objectives:

Differentiate between the two primary categories of arginine vasopressin disorder and
understand their respective pathophysiology.

Interpret the factors in evaluating a patient with suspected arginine vasopressin disorder,
including laboratory analysis.

Differentiate the treatment options for arginine vasopressin disorder, depending on the
specific etiology.

Communicate the importance of improving coordination among the interprofessional team to

enhance care for patients affected by arginine vasopressin disorder.

Access free multiple choice questions on this topic.

Introduction

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]

Terminology
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]

Etiology

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]

Epidemiology

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]
Pathophysiology

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.

Evaluation

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]

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.

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.

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.

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]
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]

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

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.

Complications

Without medical treatment, the potential DI complications include:

Chronic dehydration

Tachycardia

Decreased temperature
 Hypotension

Weight loss

Fatigue

Headaches

Kidney damage

Brain damage

Consultations

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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References

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diabetes insipidus: a clinical review. J Clin Endocrinol Metab. 2012 Oct;97(10):3426-37. [PubMed:
22855338]
2. Grace M, Balachandran V, Preethy. Menon S. Idiopathic central diabetes Insipidus. Indian J Med
Sci. 2011 Oct;65(10):452-5. [PubMed: 23511046]
3. Kalra S, Zargar AH, Jain SM, Sethi B, Chowdhury S, Singh AK, Thomas N, Unnikrishnan AG,
Thakkar PB, Malve H. Diabetes insipidus: The other diabetes. Indian J Endocrinol Metab. 2016
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