European Arginine Vasopressin Deficiency

[central diabetes insipidus] Study – the EU-AVP-D Study

Royal Victoria Hospital, Belfast

University Hospitals Birmingham

Sheffield Teaching Hospital NHS Trust

Cambridge University Hospital NHS Trust

University Hospitals of Leicester NHS Trust

Oxford University Hospitals

Arginine vasopressin (AVP) is a nine-amino acid neuropeptide released into circulation from axon terminals projecting to the posterior pituitary. AVP is the main endocrine regulator of renal water excretion to maintain fluid balance by keeping plasma volume and osmolality within narrow limits.1 Damage of the hypothalamic-pituitary axis may cause AVP deficiency, also known as central diabetes insipidus (cDI), which is clinically characterised by polyuria and consecutive polydipsia.2

Once correctly diagnosed, optimal desmopressin treatment is initiated with immediate symptomatic relief and effective long-term control of polyuria.3,4 However, if instructions to the patient on the administration of desmopressin are not accurate, dilutional hyponatraemia can develop, even in the setting of modest fluid intake.5-7 Lack of education on the correct desmopressin use might explain the high prevalence of hyponatraemia (up to 30%) in the outpatient setting.6,8 Recent data suggested the ‘desmopressin escape’ method as a simple approach to counteract this risk. This method can be described as a delay in desmopressin dose (up to several times weekly) until an aquaresis and subsequent strong thirst develops or weekly omission of a desmopressin dose.8 However, whether this method lowers the risk of hyponatraemia has not been prospectively investigated.

Even without desmopressin, patients with a functioning osmoregulated thirst perception and free access to water can compensate for urinary water loss by increased fluid intake. Therefore, hypernatraemia - an indicator of inadequate fluid intake - rarely occurs in patients with access to fluids.6,9 Critically, limited access to fluids, e.g., through the non-availability or restricted intake, can lead to life-threatening hypernatraemic dehydration. In support of this, hypernatraemia is mostly reported in hospitalised patients, presumably due to a lack of knowledge in correct fluid management and treatment failures by the medical team. Recent data reported hypernatraemic episodes in around 25% of hospitalised patients.6,8 One possible additional explanation for these observed treatment errors might be the high rate of confusion with ‘diabetes mellitus’ as recently reported in our survey study, presumably when patients with AVP deficiency are under the care of non-endocrine specialists.4 Subsequent to these unfortunate but avoidable cases of treatment errors and strong patient support for renaming the condition, a working group of representatives from international endocrinology societies now propose changing the name of ‘central diabetes insipidus’ to ‘arginine vasopressin deficiency’.8,10-13

AVP deficiency is a rare condition, and data on clinical characteristics, desmopressin-related side effects, and treatment errors or complications during hospitalisations are generally limited to small studies and case reports. We decided, together with other experts in the field, to collect data on this condition in leading European pituitary centres.

This multicentre observational cohort study aims to assess clinical characteristics and disease-related complications (e.g., the prevalence of desmopressin-induced side-effects, episodes of hypernatraemic dehydration due to inappropriate fluid management, treatment errors due to confusion with ‘diabetes mellitus’ etc.), and psychological co-morbidities. Furthermore, this study aims to prospectively evaluate over a 5-year observation period for each patient whether recent changes, such as attention to the ‘desmopressin escape’ method or renaming of the disease, might have an impact on hyponatraemia rates and in-hospital adverse events.

Hypothesis and primary objective

Data from this study will be mainly analysed explanatory. However, one of the main objectives of this study is to assess desmopressin-induced hyponatraemia.

We hypothesise that active education on the correct use of desmopressin and alerting patients on symptoms and clinical signs of hyponatraemia will reduce the rate of desmopressin-induced hyponatremia.

Therefore, the primary endpoint is to assess in a first step, desmopressin-induced hyponatremia in retrospective and to compare these data with the rate of hyponatremia in the prospective period of 5 years.

Primary and secondary endpoints

The overall endpoints of this study are to determine:

A.    Demographic characteristics (age, sex, weight, height, ethnicity)

B.    General disease-specific characteristics, including:

I.                 Cause and duration of AVP deficiency

II.               Clinical symptoms of AVP deficiency

III.              Radiographic findings related to AVP deficiency

IV.             Other diagnosed pituitary hormone deficiencies or excesses (dose and types of hormone therapies)

V.               Methods of diagnosing AVP deficiency

VI.             Current dose and type of desmopressin

VII.           Previous dose and type of desmopressin

VIII.         Use of the ‘desmopressin escape’ method

IX.             Blood/Urine laboratory

X.               Fluid and desmopressin management risk in the sub-group of patients with adipsic AVP deficiency

XI.             Complications directly related to the adipsic form of AVP deficiency (e.g., venous thrombo-embolism)

XII.           Disease course in the sub-group of patients with transient AVP deficiency

C.    In- and out-hospital complications since diagnosis

I.                 Number and setting (in- vs out-hospital) of laboratory-confirmed hyponatraemic episodes

II.               Course of plasma sodium levels during hyponatraemic episodes

III.              Involvement of endocrine specialist during hyponatraemic episodes

IV.             Complications related to hyponatraemic episodes (e.g., osmotic demyelination syndrome)

V.               Number and setting (in- vs out-hospital) of laboratory-confirmed hypernatraemic episodes

VI.             Course of plasma sodium levels during hypernatraemic episodes

VII.           Involvement of endocrine specialist during hypernatraemic episodes

VIII.         Involvement of endocrine specialist during hospitalisations for any medical and surgical reasons (planned or emergency hospitalisations)

IX.             Treatment errors during hospitalisations (e.g., wrong fluid management, missed prescription of desmopressin, wrong treatment/medication due to confusion etc.)

D.    Patients’ perspective on awareness and knowledge in the medical team

I.                 Patient-reported treatment errors during hospitalisations

II.               Patient-reported effects of the name-change of the condition

E.     Co-morbidities, including:

I.                 Current endocrine, cardiovascular, respiratory, gastrointestinal, haematological/oncological, renal, urogenital, musculoskeletal, dermatological, and neurological diseases

F.     Psychological co-morbidities, quality of life, and subjective assessment of disease control (usually not included in clinical routine)

I.                 Current and previously diagnosed psychological conditions (type, treatment, duration)

II.               Assessment of subjective symptom control using standardised questions

III.              Disease control and Quality of Life by using the Nagasaki Diabetes Insipidus Questionnaire (NDI-QoL)

IV.             Disease control and Quality of Life by using the Posterior-Pituitary Quality of Life Questionnaire (PP-QoL)

V.               Anxiety Levels assessed by using the State-Trait Anxiety Inventory (STAI)

VI.             Alexithymia by using the Toronto Alexithymia Scale (TAS-20)

VII.           Depression by using the Becks’ Depression Inventory II (BDI-II)

G.    Gynaecological and obstetric difficulties (only in female patients)

I.                 Number of children born before and after the onset of the disease

II.               Route of delivery (vaginal birth vs caesarean section [primary planned or secondary due to intra-partum complications])

III.              Need for augmentation therapies during delivery (intravenous oxytocin or prostaglandin)

IV.             Post-partum complications and difficulties (e.g., depression, haemorrhage, breastfeeding difficulties)

V.               Desmopressin dose changes during pregnancy and post-partum period

The study is designed to help scientists and doctors to improve their understanding of rare conditions and provide best care to affected children and adults. The study will also collect information directly from yourself and this will improve your doctors understanding of how the condition affects you. It is possible that, based on the information you provide, your doctor may want to discuss your condition in more detail with you.

Feb 2025 – Feb 2029 and ‘open to recruitment’

NO Data access requests bit on this project

Clinical Endocrinology Journal Foundation (CEJF) has provided funding towards this project via a grant. The project has been developed independently of CEJF.

Ferring Pharmaceuticals has provided funding towards this project via a grant. The project has been developed independently of Ferring.