26th March 2024

Diabetes Insipidus

Diabetes Insipidus

Pathophysiology

Diabetes insipidus (DI) is a condition where kidneys are unable to retain water due to the deficiency of vasopressin from the posterior pituitary gland (cranial DI) or insensitivity to its action (nephrogenic DI). Vasopressin is an antidiuretic hormone (ADH) which acts on the collecting ducts of the kidney by binding V2 receptors on the cell surface of tubular cells. This results in generation of water channels called aquaporin-2 to help reabsorption of water.

Causes

The causes of DI can be divided into central (cranial), nephrogenic, dipsogenic and gestational

Causes of cranial DI include:

• Idiopathic (often autoimmune)
• Congenital where defects in the ADH gene cause Wolfram syndrome, also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness)
• Pituitary tumours and craniopharyngiomas can cause hypopituitarism, leading to cranial DI
• Infections (tuberculosis, meningitis)
• Infiltrative conditions, including sarcoidosis
• Vascular haemorrhage
• Trauma such as head injury

Nephrogenic DI may be due to:

• Familial (vasopressin receptor gene, aquaporin-2 gene defects)
• Metabolic (low potassium, high calcium)
• Drug induced (lithium, demeclocycline)
• Chronic renal disease related (renal tubular acidosis)
• Post-obstructive uropathy

Hypothalamic disease and trauma may lead to dipsogenic DI, a form of primary polydipsia. Gestational DI occurs in pregnancy where the enzyme vasopressinase released from the placenta metabolises maternal ADH, leading to deficiency.

Clinical manifestations

Due to the lack of ADH, either from deficiency or insensitivity, the kidney tubules are unable to absorb the required amount of water that the body needs. This leads to polyuria, nocturia, polydipsia and dehydration. Symptoms of hypernatremia can occur due to the lack of dilution in the body. This presents as lethargy, thirst, weakness, irritability, confusion, coma and fits.

Diagnostics

Diagnosis of DI requires signs and symptoms with biochemistry evidence of urine and plasma osmolality. Biochemistry results that favour the diagnosis of diabetes insipidus are high or high-normal plasma osmolality with low urine osmolality, resultant high or high-normal plasma sodium (hypernatremia) and high 24-hour urine volumes. Therefore, significant DI is excluded if urine to plasma osmolality ratio is more than 2:1, provided plasma osmolality is no greater than 295mOsmol/kg.

A diagnostic test can be done with a formal water deprivation test to confirm DI. This results in failure of urinary concentration with fluid deprivation and restoration of urinary concentration with vasopressin or an analogue. In normal individuals, plasma osmolality remains normal, while urine osmolality rises above 600mOsm/kg. This is in contrast to patients with DI where plasma osmolality rises while the urine remains dilute, only concentrating after introducing an exogenous vasopressin in cranial DI and no response to vasopressin in nephrogenic DI. If cranial DI is suspected, an MRI head with pituitary function tests may be used to ascertain, treat the cause and exclude panhypopituitarism.

Management

Cranial DI

The synthetic vasopressin analogue desmopressin is the treatment of choice for cranial DI. It has a longer duration of action than vasopressin and has no vasoconstrictive effects. This can be given via three routes; orally, intranasally as a spray, and intramuscularly. Response to desmopressin must be monitored by fluid input and output chart and plasma osmolality measurements. Care must be taken to avoid water overload and consequent hyponatremia.

Nephrogenic DI

Management is based on treating the cause of nephrogenic DI. The thiazide diuretic Bendroflumethiazide can be administered to increase sensitisation of renal tubules to endogenous vasopressin. A trial of NSAIDs is encouraged to lower urine volume and plasma sodium by inhibiting prostaglandin synthase, as prostaglandins locally inhibit the action of ADH.

References

• National Institute for Health and Care Excellence (UK). Diabetes insipidus. 2022 [cited 11 January 2022]. Available from: https://www.nhs.uk/conditions/diabetes-insipidus/
• UpToDate. Urine output in Diabetes Insipidus. 2022 [cited 11 January 2022]. Available from: https://www.uptodate.com/contents/urine-output-in-diabetes-insipidus#:~:text=Diabetes%20insipidus%20(DI)%20is%20a,kidney%20effects%20(nephrogenic%20DI)
• Kumar P, Clark M. Kumar & Clark clinical medicine. Edinburgh: Elsevier Saunders; 2005. p. 992-993
• Longmore J, Wilkinson I, Baldwin A, Wallin E. Oxford handbook of clinical medicine. p. 232-233