DR AOIFE GARRAHY (Orcid ID : 0000-0001-6387-0175)

PROFESSOR CHRISTOPHER THOMPSON (Orcid ID : 0000-0003-3688-8999)

Accepted Article
Article type : Requested Review

DIAGNOSIS AND MANAGEMENT OF CENTRAL DIABETES INSIPIDUS IN ADULTS

Aoife Garrahy

Clinical Research Fellow

Academic Department of Endocrinology

Beaumont Hospital/RCSI Medical School

Dublin

Ireland

aoife.garrahy@gmail.com

Tel +35318376532

Carla Moran

Clinical Research Fellow

Academic Department of Endocrinology

Beaumont Hospital/RCSI Medical School

Dublin

Ireland

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/cen.13866
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 Christopher J. Thompson

Professor of Endocrinology
Accepted Article
Academic Department of Endocrinology

Beaumont Hospital/RCSI Medical School

Dublin

Ireland

christhompson@beaumont.ie

Tel +35318376532

SUMMARY

Central diabetes insipidus (CDI) is characterized by hypotonic polyuria due to impairment of

AVP secretion from the posterior pituitary. In clinical practice, it needs to be distinguished from
renal resistance to the antidiuretic effects of AVP (nephrogenic DI), and abnormalities of thirst
appreciation (primary polydipsia). As nephrogenic diabetes insipidus is rare in adults, unless
they are treated with lithium salts, the practical challenge is how to differentiate between CDI
and clinical disorders of excess thirst. The differential diagnosis is usually straightforward, but
the recommended gold standard test, the water deprivation test, is not without interpretative
pitfalls. The addition of the measurement of plasma AVP concentrations improves diagnostic
accuracy, but the radioimmunoassay for AVP is technically difficult, and is only available in a
few specialized centres. More recently, the measurement of plasma copeptin concentrations
have been claimed to provide a reliable alternative to measurement of plasma AVP, without the
sampling handling challenges. In addition, the measurement of thirst ratings can help the
differentiation between CDI and primary polydipsia. Once the diagnosis of CDI is biochemically
certain, investigations to determine the cause of AVP deficiency are needed. In this review, we
will outline the diagnostic approach to polyuria, revisit the caveats of the water deprivation test,
and review recent data on value of adding AVP/copeptin measurement. We will also discuss
treatment strategies for CDI, with analysis of potential complications of treatment.

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 KEYWORDS

Diabetes insipidus, copeptin, vasopressin

Accepted Article
INTRODUCTION

Diabetes insipidus (DI) is a rare disorder of water homeostasis characterized by the excretion of
abnormally large volumes of hypotonic urine. Over 90% of the vasopressinergic neurons which
project from the supraoptic and paraventricular nuclei to terminate in the posterior pituitary
must be destroyed in order to produce AVP deficiency sufficient to cause polyuric symptoms.
Central DI (CDI) therefore always represents significant hypothalamo-neurohypophysial
dysfunction.

The diagnostic challenge for the clinician is to confirm the presence of polyuria and then
forensically distinguish between the three main disease processes which lead to excess, dilute,
urine. Polyuria can result from abnormalities in any of three fundamental components of the
physiological control of water balance;

1. Subnormal vasopressin secretion, or central diabetes insipidus (CDI), which reflects

hypothalamic or posterior pituitary damage.
2. Impaired renal concentrating ability in response to AVP (nephrogenic DI, NDI).
3. Excessive thirst appreciation (primary polydipsia, PP).

The differentiation between the causes of polydipsia is clinically important as the diagnosis
dictates the treatment recommended to the patient. It is particularly important not to
misdiagnose primary polydipsia as CDI, as inappropriate therapy with desmopressin can lead to
dangerous hyponatraemia in patients who continue to drink excessively.

In this review, we will summarise the various diagnostic tests used to make the biochemical
diagnosis of CDI, and the biochemical and radiological tests needed to identify the causation of
AVP deficiency. We will also review the treatment strategies to manage polyuria, while avoiding
hyponatraemia.

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Accepted Article
CAUSES OF CENTRAL DIABETES INSIPIDUS

Central DI is the clinical manifestation of destruction of the neurons of the

hypothalamus/posterior pituitary axis, with consequent loss of AVP secretion. The syndrome is
caused by a wide variety of acquired or congenital lesions.

The vast majority of CDI cases in our unit occur secondary to neurosurgical conditions (table 1).
Pituitary tumours almost never cause CDI de novo, but DI occurs in 20% of patients following
transsphenoidal surgery, due to interruptions in the hypothalamic-neurohypophyseal neuronal
connections. DI is typically transient, occurring within 24 – 48 hours of surgery, and settles
within 2-5 days; persistent DI is rare 1. Rarely, a triphasic response can occur in which initial DI
is followed by a transient period of hyponatraemia and antidiuresis, due to unregulated release
of AVP from degenerating neurohypophyseal tissue. This is followed by a return to permanent
DI up to two weeks postoperatively when AVP stores are depleted, and neurones undergo
gliosis. As pituitary adenomas do not present with DI, the coexistence of DI with a sellar mass
suggests an alternative diagnosis, such as craniopharyngioma, pinealoma or germinoma, or a
granulomatous process. Metastases from distant tumours are occasionally found in the
pituitary stalk. Most are asymptomatic, but if they do cause hormonal disturbances, CDI is the
commonest manifestation.

DI occurs in the acute phase of TBI in 20% of cases 2,3, and in 15% of patients with SAH 4. DI is
almost always transient, and in both conditions, persistent DI is associated with worse
prognosis; persistent DI is a common manifestation of increasing intracranial pressure and may
presage the onset of coning 3. Careful follow up shows that DI persists in only 7% of TBI
survivors, most of whom do not have polyuria which needs treatment with desmopressin 5.

In panhypopituitarism, DI may not initially clinically manifest, as steroid deficiency impairs free
water excretion. Polyuria may only be unmasked when coexisting cortisol deficiency is treated 6.

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 While traditionally up to 50% of cases of DI were considered to be idiopathic 7; many of these
Accepted Article
are now thought to be autoimmune in nature. Early work by Scherbaum and Bottazzo
demonstrated positive AVP cell antibodies in one third of a cohort of patients with idiopathic DI
recruited from a number of academic centers in London 8. They later reported rates of overt
autoimmune disease in 28% of a similar cohort and similar rates were subsequently confirmed
by other groups; pernicious anaemia and thyroid disease are most common 9-11.

Adipsic DI

Adipsic DI is a rare disorder, characterized by AVP deficiency which is complicated by failure to

generate thirst sensation in response to hypernatraemia. Loss of thirst sensation leads to
inadequate compensatory water intake, which renders the patient vulnerable to significant
hypernatraemia. Adipsic DI is classically described following neurosurgical clipping of anterior
communicating artery (ACOM) aneurysms following SAH, as the osmoreceptors in the
hypothalamus derive their vascular supply from small perforating branches of the ACOM 12. It is
also relatively common after extensive surgery for large craniopharyngiomas 13 and
occasionally after surgery for suprasellar tumours, or after neurosarcoidosis 14, or TBI 12.

Recovery of thirst is unusual, with few well-documented cases in the literature 15.

DIAGNOSIS OF CENTRAL DIABETES INSIPIDUS

History and clinical examination

History and clinical examination occasionally yield useful diagnostic clues. A history of lithium
therapy may raise the possibility of NDI, whereas previous brain injury or neurosurgical
intervention may indicate CDI. A careful family history is important, not only to identify
members of rare kindreds with inherited DI, but also to identify autoimmune endocrine disease,
which could suggest autoimmune CDI. Erectile dysfunction, menstrual disturbances and fatigue
may be clinical manifestations of hypopituitarism. Examination is usually normal, but clinical
signs of hypogonadism, such as loss of body hair and atrophy of sexual secondary
characteristics, could indicate pituitary disease and loss of temporal visual fields would raise
the possibility of an intracranial tumour, most likely a craniopharyngioma.

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 The first step in diagnosis is to confirm the presence of hypotonic polyuria. Approximately 15%
Accepted Article
of patients referred for investigation of polyuria have normal urine volume, but present with
urinary frequency, due to infection, prostatism or irritable bladder. In an adult patient, if the
daily urine volume is less than 2.5 litres no further investigations of osmoregulatory function
are required, though urological referral may be indicated.

Once polyuria is confirmed on 24h urine volume, diabetes mellitus, renal impairment,
hyperglycaemia, hypercalcemia and hypokalemia should be excluded by baseline laboratory
tests. A dipstick urine may reveal evidence of renal disease or infection, so this is an essential
clinic investigation. Urine osmolality is low in all forms of polyuria, but if the clinic
measurement is greater than 700 mOsm/kg, this indicates good plasma concentrations of AVP,
and the patient can be reassured that they do not have CDI without further investigations. A
number of aspects of clinical history raise the possibility of PP;

1. If the patient has daytime symptoms but has an uninterrupted night’s sleep
2. If the patient wakes at night with the need to drink rather than to pass urine
3. If there is associated psychiatric disease; polydipsia is particularly associated with
schizophrenia

In contrast, an abrupt recent onset of polyuria and polydipsia is characteristic of idiopathic or

autoimmune CDI.

The clinic plasma sodium concentration can give useful clues to the differential diagnosis.
Although plasma sodium is almost always normal at diagnosis in CDI, plasma concentrations at
the upper end of the normal reference range are more usual in CDI than in PP. In contrast, as PP
patients need to lower plasma osmolality to below the osmotic threshold for AVP secretion 16 in
order to produce polyuria, plasma sodium in PP patients is almost invariably at the lower end of
the reference range.

It is rarely possible to make an outpatient differential diagnosis between CDI, NDI and PP
because of the substantial crossover of baseline measurements of plasma sodium, osmolality
and urine osmolality. In the majority of cases the differential diagnosis of polyuria therefore

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 requires dynamic testing of the AVP-renal axis, of which both indirect and direct methods are
possible.
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Indirect tests

The most commonly used test for DI is the two step water deprivation test. The first step is an
eight hour period of water deprivation; the physiological basis for this step is that dehydration
stimulates the secretion of vasopressin, with consequent reduction in free water clearance.
Urine volumes fall and urine osmolality should rise to over 750 mOsm/kg, provided that a
sufficient osmotic stimulus to AVP secretion (plasma osmolality > 295 mosm/kg) is attained at
the conclusion of dehydration. This step should differentiate patients with primary polydipsia,
in whom vasopressin secretion and function are normal, from patients with either central and
nephrogenic diabetes insipidus, who do not concentrate urine at the end of dehydration.

The second part of the test is designed to differentiate central diabetes insipidus from
nephrogenic diabetes insipidus. Desmopressin (dDAVP), an AVP analogue, is administered by
intramuscular or subcutaneous injection, and the urine osmolality response is measured. As
patients with central DI are simply missing AVP, they respond to exogenous desmopressin with
a rise in urine osmolality to over 750 mOsm/kg. Patients with nephrogenic DI are resistant to
the antidiuretic effects of desmopressin and do not respond with urinary concentration. In the
assessment of pituitary function after neurosurgery, the second step - administration of
desmopressin - is unnecessary, as the test is simply establishing the presence or absence of CDI.

The interpretation of this test is shown in table 2.

Although the interpretation of the water deprivation test is theoretically straightforward, there
are a number of issues which make the test unwieldy and which may produce erroneous
diagnoses. The test is best performed in a specialised centre. Patients should be encouraged to
hydrate prior to the test to prevent over-aggressive dehydration. This is particularly important
for patients with marked polyuria, as a patient with severe CDI may dehydrate quickly when
fluid is withheld. In addition, if the patient is suspected to have adipsia, an urgent plasma
osmolality measurement should be requested prior to water deprivation, to ensure that the test

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 does not commence when the patient is already dehydrated. To prevent over dehydration and
severe hypernatraemia, patients should be weighed at baseline, and two hourly thereafter; a
drop in body weight of 5% from baseline indicates serious loss of body water, and the test
Accepted Article
should be abandoned. Patients with severe polyuria despite water restriction should also have
interim urgent electrolyte measurements. Water deprivation tests require careful supervision
to ensure that surreptitious drinking does not occur, particularly in patients with suspected
dipsogenic DI.

While the water deprivation test may differentiate between PP, CDI and NDI in classical and
complete cases, a number of osmoregulatory subtleties make differentiation between PP, partial
CDI and NDI challenging.

a) Subjects with long standing polydipsia may not concentrate urine after administration
of dDAVP. Prolonged suppression of AVP secretion, by chronic overdrinking means that
V2 receptor stimulation does not occur, and pre-formed AQ-2 is scarce. As a result, some
patients with PP do not respond to endogenous or exogenous antidiuretic hormone, and
can be misclassified as partial NDI 17.
b) In patients with partial CDI, lower than normal AVP concentrations can lead to urinary
concentration 18, possibly due to up-regulation of V2 receptors.
c) In NDI, high AVP concentrations achieved in WDT can partially overcome renal
resistance to AVP, resulting in concentration of urine > 300 mOsm/kg, leading to
diagnostic confusion 19.

As a consequence, an overlap in results between patients with PP, CDI and NDI leads to
uncertain diagnostic accuracy of the WDT. It should be further noted that the diagnostic criteria
recommended for interpretation of the WDT are based on only 36 patients 20. Until recently,
the sensitivity and specificity of the results of the WDT had not been validated, but a recent
prospective study showed that the correct diagnosis was made in only 70% of patients. In
patients with primary polydipsia, the correct diagnosis was made in only 41% of cases 21.

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 Direct tests
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Measurement of AVP

With the introduction of the first sensitive and specific radioimmunoassay for AVP in 1973 22, it
was hoped that incorporation of AVP measurement would compensate for the diagnostic pitfalls
of the standard WDT. Early studies 23,24 demonstrated that diagnoses provided by the standard
WDT were improved by the incorporation of measurement of plasma AVP concentration.
However, the significant pre-analytical and methodical limitations of the AVP assay have limited
widespread use of the method. The hormone is unstable and needs careful sample handling,
immediate centrifugation, and storage at -70C. In addition, commercial antibodies for use in
radioimmunoassays are poorly sensitive, and have lower limits of detection for the hormone
which exceed physiological plasma concentrations. Sensitive and specific assays are relatively
uncommon 25. An analysis by Fenske has more recently shown a diagnostic accuracy of only
46% when direct AVP measurement was prospectively tested in 50 patients with polyuria who
underwent WDT 21, though these results may reflect both suboptimal osmotic stimulation and
analytical limitations of the AVP assay.

If the WDT does not produce a firm diagnosis, measurement of the AVP responses during the
intravenous infusion of hypertonic (3-5%) sodium chloride solution can help distinguish
between CDI and NDI or primary polydipsia 26. Hypertonic saline infusion does ensure maximal
stimulation of AVP secretion. Figure 1 indicates the relationship of plasma osmolality to plasma
AVP during hypertonic saline infusion, in patients with varying causes of polyuria. Patients with
NDI or PP will have AVP responses in the normal range, while subnormal AVP responses are
diagnostic of CDI 27. Patients with severe AVP deficiency may become hypernatraemic during
this test, which should only be performed under specialist supervision.

Measurement of copeptin

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 As the technical issues of plasma AVP measurements are substantial, the measurement of
plasma copeptin has been proposed as a surrogate for measurement of plasma AVP. Copeptin is
the C-terminal locus of the AVP precursor, prepro-vasopressin, and it is co-secreted from the
Accepted Article
neurohypophysis in equimolar amounts with AVP, in response to osmotic and haemodynamic
stimuli (figure 2). It is much more stable ex vivo, so sample handling is straightforward; plasma
sample size is also much smaller. A sandwich immunoluminometric assay has demonstrated
robust performance, with a lower limit of detection of 0.4 pmol/L. Physiological studies have
revealed the copeptin responses to changes in plasma osmolality are similar to those seen with
pAVP 28,29 (figure 3). Studies have also claimed that measurement of the copeptin response to
insulin tolerance test can predict CDI 30. The same group have also demonstrated, in a
prospective multicenter study, that a post-transsphenoidal surgery co-peptin concentration of <
2.5 pmol/L had a predictive value of 81% for CDI, with a specificity of 97% 31.

In a prospective study of 55 patients, the Swiss group further demonstrated that a baseline
plasma copeptin concentration of > 21.4 pmol/L differentiates NDI from other causes of
polyuria, with a sensitivity and specificity of 100%, thus mitigating the need for WDT in this
circumstance. Conversely, a baseline copeptin < 2.6 pmol/L diagnoses complete CDI with 95%
sensitivity and 100% specificity. In cases where baseline copeptin is 2.6 - 21.4pmol/L, an
osmotically-stimulated copeptin concentration > 4.9 pmol/L reliably discriminated between PP
and cDI 32. In their followup, much larger, study published earlier this year in the NEJM (n=156),
this pre-determined stimulated copeptin cutoff of 4.9 pmol/L had a 93% sensitivity and 100%
specificity to distinguish between primary polydipsia and CDI. The overall diagnostic accuracy
of the hypertonic saline test was 96%, far superior to that of the WDT, 77%, the main caveat
being a higher rate of reported adverse events related to the hypertonic saline test 33. The
addition of copeptin to the standard WDT did not improve it’s diagnostic accuracy.

In summary, copeptin is a promising marker of plasma AVP concentration, which offers a

convenient, rapid and sensitive diagnostic tool for polyuric states. The assay should be
manageable in most reputable laboratories so that it is likely to replace measurement of plasma
AVP in routine diagnostic practice.

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 Measurement of thirst
Accepted Article
Measurement of thirst, using a simple 10 cm long, unmarked visual analogue scale, has shown in
physiological studies that thirst onset occurs at the same osmotic threshold as for AVP secretion
16. Thirst is rapidly switched off by drinking34, even though hyperosmolarity persists. The
characteristics of osmoregulated thirst are surprisingly reproducible within an individual,
though there is considerable intra-individual variation 35. Thirst responses in CDI show a
physiological pattern of linear elevation during osmotic stimulation, and suppression after
drinking 36.

Measurement of thirst is of diagnostic value in two scenarios. In adipsic DI, the demonstration
of absent osmoregulated thirst during WDT or hypertonic saline infusion, is the gold standard
for diagnosis of the condition 12,36. In addition, patients with primary polydipsia have three
clearly defined abnormalities of thirst; a low osmotic threshold for thirst, exaggerated thirst
responses to elevation of plasma osmolality, and failure to suppress thirst during drinking, after
osmotic stimulation 37. It is the last of these three abnormalities which is diagnostically helpful,
as failure to suppress thirst by more than 50% of stimulated levels, after drinking, is the
strongest diagnostic indicator of primary polydipsia (Thompson CJ, unpublished observations).

FURTHER INVESTIGATIONS

Once a diagnosis of CDI is made, MRI imaging of the hypothalamo-pituitary region is required to
establish whether there is a structural lesion which is responsible for AVP deficiency. It is
important to note that lesions such as histiocytosis and germinoma, may not manifest on the
initial scans; normal imaging should be repeated within six months 38. More frequent imaging is
recommended in children with isolated DI, in whom germ cell tumours are more likely 39.

Elevated serum and CSF AFP and BHCG may serve as markers for germ cell tumours, although
they do lack sensitivity 40. Germinomas may present with normal AFP levels in both serum and
CSF, and normal or mildly elevated BHCG levels 41.

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 The classic MRI finding in CDI is loss of the posterior pituitary bright spot. Some authors argue
that the persistence of a pituitary bright spot does not necessarily outrule a diagnosis of CDI
42,43. A multicenter review of 39 patients with CDI, in whom the diagnosis was based on either
Accepted Article
WDT, or the AVP response to hypertonic saline infusion, demonstrated loss of the pituitary
bright spot in only two-thirds of cases 11. In addition, as the intensity of the physiological bright
spot attenuates with age, absence of signal may occur in 20% of the elderly population 44. The
second most common MRI abnormality encountered in CDI is thickening or enlargement of the
pituitary stalk. The differential diagnosis of stalk thickening includes small craniopharyngiomas,
lymphocytic hypophysitis, infiltrative disorders, autoimmune DI, metastases, and, particularly
in children and young adults, germinoma. The diagnosis of Langerhans cell histiocytosis, may
be supported by clinical and radiological signs of systemic histiocytosis, and anterior
hypopituitarism.

Baseline dynamic assessments of anterior pituitary function should be performed, with deficits
most likely where there is a structural cause for CDI. Patients with idiopathic DI should be
screened for co-existing autoimmune conditions, particularly thyroid disease, type 1 diabetes
and pernicious anaemia 11.

ASSESSMENT OF ADIPSIC DI

Adipsic DI usually occurs in patients who have structural damage to the anterior hypothalamus
where the osmoreceptors are situated. It has most often been reported following after clipping
of anterior communicating aneurysms or after extensive surgery for craniopharyngiomas,
though a wide variety of aetiologies have been reported in the literature 45. The hypothalamic
damage is not confined to the osmoreceptors; a number of other hypothalamic abnormalities
co-exist with the DI, including obstructive sleep apnoea, hypothalamic obesity, abnormal
temperature regulation and seizure disorders 12.

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 TREATMENT
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Treatment of diabetes insipidus involves replacement of the free water deficit, replacement of
the deficient hormone (in the case of CDI), and treatment of the underlying condition. AVP has a
half-life in plasma of 5-10 minutes, too short for practical use. dDAVP is a synthetic analogue
specific for the V2 receptor, which has been modified from AVP in two ways; the amino group of
the cysteine has been removed to prolong half-life 46, and D-arginine has been substituted for L-
arginine to eliminate pressor activity 47. It is available in parenteral, oral and nasal forms; the
bioavailability of the parenteral form is 100 times that of the oral form, so that typical doses are
1 – 4mcg subcutaneously and 100 – 400mcg when given orally. The nasal form has a quicker
onset of action, however its effectiveness may be reduced if there is nasal mucosa inflammation.
Most patients prefer the oral preparation as the more convenient option.

Acute DI

Acute onset of CDI usually occurs in the neurosurgical setting, two to three days following
hypothalamic/pituitary insult. Hypernatraemia can ensue if the patient has impaired cognition,
absent thirst or cannot freely access water because of immobility. Urinary water loss should be
clamped by administrating desmopressin (dDAVP), and water deficit should be replaced with
hypotonic fluids. Acute CDI is usually transient and often responds to a single dose of parenteral
dDAVP 48. Further doses are administered only if polyuria recurs. Rarely, a triphasic response
can occur, in which initial DI is followed by an antidiuresis and hyponatraemia, with a
subsequent return to permanent DI. For this reason, and due to the fact that CDI is often
transient, regular dDAVP is only prescribed if polyuria persists beyond 48 hours, with ongoing
monitoring of pNa and urine volume advised 49. Withdrawal of dDAVP prior to discharge from
hospital is useful in identifying recovery of endogenous AVP secretion. Patients who are
discharged on dDAVP should be advised about the potential risk of the triphasic response, and
the need for urgent blood draw for pNa measurement should they develop symptoms
suggestive of hyponatraemia, such as headache and bloating.

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 Chronic DI

Long-term treatment with desmopressin (dDAVP) can control the thirst and polyuria of CDI
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and, in the absence of other pituitary hormone deficiencies, can allow the patient a normal
quality of life. The dose of dDAVP required is proportional to the degree of AVP deficiency. In
patients with mild CDI, a starting dose of 100 – 200mcg orally at night is often sufficient to
control nocturia. The dose may be titrated until symptom control is achieved; severe disease
may require up to 200mcg two to three times daily.

Hyponatraemia is a relatively common complication of dDAVP treatment of CDI. In normal

physiology, water drinking suppresses endogenous AVP to allow excretion of excess free water
and maintenance of eunatraemia. However, pharmacological vasopressin analogues are non-
suppressible. Water intake which is in excess of physiological needs cannot be lost through the
kidneys and accumulates, causing dilutional hyponatraemia. A retrospective review of 147
outpatients with CDI, demonstrated that mild hyponatraemia (pNa 131 – 134 mmol/L)
occurred in 27% of patients with CDI, while 15% had more significant hyponatraemia (pNa ≤
130 mmol/L). The risk of hyponatraemia was higher in patients with more severe DI, who
needed higher doses of regular dDAVP 50. Chronic hyponatraemia is associated with unsteady
gait, falls, fractures, and increased mortality 51, so the maintenance of normal plasma sodium
concentrations is important.

The paper additionally reported that 5% of patients had been admitted to hospital with
hyponatraemia secondary to dDAVP therapy, so the effects of over-treatment are not trivial. The
key to avoiding hyponatraemia is to allow regular periods of free water clearance, so that excess
water does not build up. There are several ways to achieve this;

1. To delay a dose of dDAVP once or twice per week to allow an aquaresis to occur. The
patient waits until an aquaresis has established – two or three visits to the toilet – and
then they take the subsequent tablet. This is highly effective, and is the most popular
with patients.
2. To delay each tablet of desmopressin until a slight aquaresis is evident. This method is
extremely effective as there is a constant renal clearance of excess water. Some patients
prefer a regular minor inconvenience to having to set aside an entire morning during
which they pay several visits to the bathroom.

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 3. To omit a tablet once a week. This an effective method, but patients are reluctant to
submit themselves to an entire day of polyuria.
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In ambulant patients, hypernatraemia is almost exclusively a complication seen in adipsic DI; it
is very rare in the vast majority of patients with intact thirst. In Behan’s study, patients with
abnormal thirst were much more likely to develop significant hypernatraemia as out-patients,
when compared to patients with intact thirst appreciation (20% vs. 1.4%, p=0.02) 50.

Hospitalisation with intercurrent illness further compounds the risk of dysnatraemia in patients
with DI. Water intake may be impaired due to vomiting, diminished consciousness level, or
fasting. Administration of solute-free fluids is essential if the patient is unable to maintain an
adequate oral intake, and should be accompanied by close monitoring of fluid balance, weight
and electrolytes 45. In Behan’s study, three out of every four patients with dDAVP-treated DI
had abnormal plasma sodium concentrations during a subsequent neurosurgical admission,
with the most common abnormality being mild hypernatraemia. Serious hypernatraemia is a
particular feature in adipsic DI; 50% of patients with CDI and disordered thirst developed
significant inpatient hypernatraemia (pNa > 150 mmol/L). These data emphasise the challenge
that remains in managing fluid balance, even in centers with experience in managing adipsic DI.

Patients with diabetes insipidus who are required to fast for a procedure warrant specialist
supervision as dehydration will quickly ensue if dDAVP is not given and the patient
concomitantly fasted. If oral medication is not allowed, parenteral dDAVP should be given
perioperatively and maintenance isotonic fluids administered for as long as the patient is
fasting, with regular checks of plasma sodium (e.g. 6 hourly). Over-zealous administration of
intravenous fluids should also be avoided, as this can lead to hyponatraemia due to the non-
suppressibility of the antidiuretic effect of dDAVP.

Another scenario which warrants special mention is alcohol consumption, in particular beer
drinkers who may quickly consume large volumes of hypotonic fluid. In healthy individuals,
ethanol suppresses AVP secretion, leading to an aquaresis; this suppression does not occur in
dDAVP-treated patients, leaving them at risk of dilutional hyponatraemia.

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 CONCLUSION
Accepted Article
The diagnosis of DI is an often cumbersome one, made challenging by the pitfalls of the water
deprivation test. Recent prospective multicenter trial data on copeptin measurement suggests
this surrogate marker improves diagnostic accuracy in polyuric syndromes and it’s
measurement after hypertonic saline infusion may soon become part of routine diagnostic
algorithms, in specialised centers. While the treatment of central DI has not changed in recent
decades; our appreciation of associated complications has. Patients with adipsic DI are at
significant risk of hypernatraemia and management of this condition can be particularly
challenging. On the other hand, hyponatraemia is a relatively common consequence of dDAVP
treatment in those with intact thirst.

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 Table 1: Aetiology of CDI

Normal thirst CDI Abnormal thirst CDI

Accepted Article
n=137 n=10
Diagnosis Craniopharyngioma n=40 Craniopharyngioma n=5
Non-functioning adenoma, (post- Prolactinoma n=1
op) n=40 Rathke’s cyst n=1
Secretory tumour, post-op Hypothalamic syndrome n=1
n=20 Infiltrative n=1
Idiopathic/autoimmune n=12 Vascular n=1
Infiltrative n=7
Other tumour n=7
Vascular/TBI n=6
Apoplexy n=5

Causes of CDI in 147 patients included in the Beaumont Hospital Pituitary Database. Adapted
from Behan LA, Sherlock M, Moyles P, et al. Abnormal plasma sodium concentrations in patients
treated with desmopressin for cranial diabetes insipidus: results of a long-term retrospective
study. European journal of endocrinology. 2015 50

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Accepted Article
Table 2: Interpretation of WDT

Osmolalities post water deprivation Post dDAVP urine

(mOsm/kg) osmolality
(mOsm/kg)
Plasma Urine

Normal 283-293 >750 >750

Central DI >293 <300 >750

Nephrogenic DI >293 <300 <300

Partial DI or primary >293 300-750 <750

polydipsia

Responses to water deprivation and subsequent dDAVP in central DI, nephrogenic DI and
primary polydipsia.

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 Figure 1 Title

AVP responses to hypertonic saline in polyuric patients

Accepted Article
Legend

Relationship of plasma osmolality to plasma AVP during hypertonic saline infusion in eight
patients with CDI (open circles), three patients with NDI (closed circles), and three patients
with primary polydipsia (triangles). The shaded area represents the range of normal responses
in 40 healthy volunteers. LD represents the limit of detection of the AVP assay. With permission,
from Thompson CJ. Polyuric states in man. Bailliere's clinical endocrinology and metabolism.
1989;3(2):473-497 18.

Figure 2:

Title

Structure of vasopressin pre-pro-hormone

Figure 3:

Title

Correlation of plasma copeptin and vasopressin concentrations

Legend

Correlation of plasma copeptin and vasopressin concentrations measured during individual

water load-hypertonic saline tests in 20 healthy volunteers. rs denotes Spearman’s rank
correlation coefficients. With permission, from "Correlation of plasma copeptin and vasopressin
concentrations in hypo-, iso-, and hyperosmolar States." J Clin Endocrinol Metab 96(4): 1046-
1052

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Accepted Article

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.