Nephrogenic Diabetes Insipidus

Synonyms: NDI, Insensitivity to Anti-Diuretic hormone (ADH)/Arginine Vasopressin (AVP)

See also: Diabetes insipidus article.

Diabetes insipidus is a condition caused by hyposecretion of, or insensitivity to the effects of, Anti-Diuretic Hormone (ADH), which regulates plasma osmolarity by altering the reabsorption of water in the cortical and medullary collecting tubules of the kidney. This process is governed by osmoreceptors in the supra-optic nucleus of the hypothalamus that regulate ADH secretion. The condition can occur in cranial or central form (CDI) or nephrogenic form (NDI). The cranial form is due to the impaired secretion of ADH, usually due to a primary intracerebral pathology affecting hypothalamic function. This is discussed in a separate article.

Inherited NDI is caused by a genetic defect leading to a fault in the ADH receptor-protein, or in the protein that mediates its effects on the renal tubules. It may also be acquired (the commonest form), due to the effects of renal disease/drugs/metabolic abnormalities etc. on the renal tubules. It causes the passage of copious amounts of dilute urine (usually >3l/24hrs with urine osmolarity <300 mOsm/kg).

The condition is moderately rare. Overall combined prevalence of CDI and NDI combined is estimated at 1 in 25,000 people in the USA.⁸ Acquired forms of NDI are commoner than genetic forms. In patients treated long-term (15 years or more) with lithium salts for mood disorders, prevalence of NDI is estimated at around 10%. It is important for those who supervise or prescribe lithium therapy to be aware of this serious complication and to monitor for it on a yearly basis by enquiring about symptoms and checking 24-hour urinary volumes.¹ Once NDI has become severe or established in a patient on lithium, it may not improve after drug discontinuation, and so its early recognition is important.

Symptoms

The onset of symptoms can be vague and insidious, such that the sufferer may suspect nothing untoward, despite having a urinary volume that would be very troubling had it come on acutely. Patients may experience marked polyuria and can pass urine up to every half-an-hour. Polydipsia and chronic thirst are usually a feature and there may be a predilection for very cold drinks, and usually water. Nocturia occurring several times per night is common, particularly in older adults. Children may develop nocturnal enuresis, where they have previously been continent. Infants may present with irritability, failure to thrive, protracted crying, anorexia and fatiguability or feeding problems. If there is damage to the bladder through chronic overdistension, then urinary incontinence may ensue. This is a particular problem in those who suffer inborn causes of NDI, particularly AQP2 mutations.⁶

Signs

There may be signs of dehydration and the bladder can be grossly enlarged and palpable. 24-hour urinary collection will show urine volume >3l/24 hrs.

• Psychogenic or primary polydipsia (PP)
• Diabetes mellitus
• Other osmotic diureses
• Diuretic abuse

Check plasma glucose, U&E and urine/plasma osmolarity and any other relevant electrolytes such as calcium. If glucose and electrolytes are normal then the fluid deprivation test and response to desmopressin is used to categorise the cause of diabetes insipidus and distinguish it from its differential diagnoses. The patient is deprived of fluids for up to 8 hours or until 5% loss of body weight – then desmopressin (DDAVP) 2g IM given. The table below illustrates correct interpretation of the results.

• If available/necessary, then plasma vasopressin levels and osmolarity in response to infusion of 5% hypertonic saline at 0.05 ml/kg/min for 2 hours can aid diagnosis. Alternatively, try a therapeutic trial of low-dose desmopressin with careful monitoring of plasma osmolarity or serum sodium. CDI patients improve, those with NDI are unaffected and those with PP develop hyponatraemia and may stop drinking.
• Renal tract US or IVP may be used to assess for obstructive complications caused by the high urinary back-pressure.

• If daily urine volume is <4l/24hrs and the patient is not suffering from severe dehydration then definitive therapy is not always necessary.
• It is important for patients to always have access to drinking water and to drink enough to satiate their thirst.
• Correct any metabolic abnormality.
• Stop any drugs that may be causing the problem.
• High-dose DDAVP may be used with success in mild to moderate cases of NDI.
• In severe cases then other medications such as indomethacin, chlorpropamide, carbamazepine, clofibrate and thiazides may be given as a trial but their efficacy is limited.
• Patients with NDI undergoing surgery need careful multi-disciplinary management with close attention to fluid regimens and DDAVP administration.⁹
• Patients with genetic causes or severe NDI may need to practise clean, intermittent catheterisation to reduce urinary tract back-pressure complications.⁶

DDAVP can worsen myocardial ischaemia in susceptible patients; there may be a need for nitrates/other anti-anginals. Patients with diabetes insipidus need careful monitoring of fluid balance and therapy following surgery, with multidisciplinary care.⁹ Patients with genetic causes are prone to bladder dysfunction and hydroureter/hydronephrosis if the condition is undiagnosed or untreated for an appreciable period of time.⁶

Outlook usually good once treatment or correct fluid management has been instituted. Specialist follow-up is required to monitor for complications and response to therapy. Patients with inborn errors are more likely to suffer complications as the underlying cause cannot be removed.

It is important to monitor for this complication of lithium use through at-least annual review of symptoms of NDI and 24-hour urinary volume measurement. Patients on lithium should be made aware of this potential complication and warned about symptoms that should prompt them to seek medical review.¹