Polyuria after head injury: diabetes insipidus, diabetes mellitus or primary polydipsia?
A 24-year-old man is admitted after three weeks of passing 7-9 L of urine a day and drinking constantly, including at night. Six months earlier he had a road accident with a base-of-skull fracture. Examination: pulse 104/min, blood pressure 104/70 mmHg, dry mucous membranes. Investigations: fasting plasma glucose 92 mg/dL, no glucose or ketones in urine, serum sodium 149 mmol/L, serum osmolality 302 mOsm/kg, urine osmolality 88 mOsm/kg, urine specific gravity 1.003. A supervised water deprivation test is performed. After 4 hours, urine osmolality is still 86 mOsm/kg while body weight has fallen 3.2% and serum sodium has risen to 152 mmol/L. Two hours after 2 micrograms of desmopressin subcutaneously, urine osmolality rises to 510 mOsm/kg and urine volume falls sharply. The resident proposes 2 L of intravenous 0.9% saline and restriction of oral fluids.
1. Interpret the results, name the diagnosis and the physiological defect, and explain why the resident's plan is inappropriate.
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Interpreting the numbers. Polyuria with a dilute urine (88 mOsm/kg) in the face of a raised serum sodium and osmolality means the kidney is losing water, not solute: a solute diuresis such as diabetes mellitus is excluded by the normal glucose and absent ketones. The failure to concentrate during water deprivation shows that the concentrating mechanism is not working. A patient with primary polydipsia would usually concentrate during deprivation, because their ADH axis is intact. The rise in urine osmolality from 86 to 510 after desmopressin shows that the collecting ducts respond to an ADH analogue, so the kidney itself is competent. The defect is therefore failure of ADH secretion - cranial (central) diabetes insipidus, consistent with the base-of-skull fracture damaging the hypothalamo-hypophyseal tract.
Why the plan is wrong. This patient has a pure water deficit, not a salt deficit or volume depletion. Infusing 0.9% saline adds sodium and worsens hypernatraemia; restricting fluids in someone losing litres of dilute urine is dangerous. The correct approach is to replace free water (oral or nasogastric water, or 5% dextrose/hypotonic saline if needed) together with desmopressin, correcting serum sodium slowly - no faster than about 10 mmol/L per 24 hours - because rapid correction risks cerebral oedema. A rough free-water deficit for a 70 kg man at sodium 152 mmol/L is about 3.5 L, given gradually.
2. Explain, at the cellular level, how desmopressin corrects the urine-concentrating defect, and why a V2-selective analogue is used rather than ADH itself.
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Normal mechanism. ADH released from the posterior pituitary binds V2 receptors on the basolateral membrane of principal cells in the collecting duct. V2 is a Gs-coupled receptor: it activates adenylyl cyclase, raises intracellular cAMP, and activates protein kinase A. This triggers exocytosis of vesicles carrying aquaporin-2 water channels into the apical membrane, and phosphorylation of existing channels. Water then moves down the medullary osmotic gradient from lumen to interstitium, and is removed by the vasa recta, so urine is concentrated. When ADH is absent, aquaporin-2 stays in intracellular vesicles and the collecting duct is water-impermeable.
Desmopressin's action. Desmopressin is an analogue of ADH that binds V2 receptors, so the same cAMP-aquaporin-2 cascade is restored and water reabsorption returns. Because it is V2-selective, it avoids the V1-mediated vasoconstriction and uterine contraction produced by ADH, and because it is structurally modified it resists enzymatic degradation, giving a longer duration of action. The 510 mOsm/kg response in this patient is exactly the expected response, and it is also the evidence that the defect lies upstream of the receptor.
3. What monitoring does desmopressin therapy require, and how can the treatment itself harm the patient?
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The hazard is hyponatraemia. Desmopressin removes the kidney's ability to excrete free water. If the patient keeps drinking large volumes out of habit - which this man has done for weeks - retained water dilutes the serum sodium and can cause headache, nausea, confusion, seizures and cerebral oedema. He must be told to drink only to thirst, not by habit, and intake and output should be recorded.
Monitoring plan.
- Serum sodium and osmolality at baseline, then daily while the dose is stabilised, and whenever symptoms or fluid intake change.
- Daily weight and a strict fluid balance chart; a rising weight with falling sodium is the warning pattern.
- Urine output and urine osmolality to confirm the dose is adequate without being excessive.
- Review of the dose during intercurrent illness, hot weather or vomiting, when intake falls.
Before and during diagnosis. Other causes of polyuria should be excluded before committing to lifelong therapy - uncontrolled diabetes mellitus, hypercalcaemia, hypokalaemia, and, importantly, untreated adrenal insufficiency or hypothyroidism, which impair free-water clearance and can unmask severe hyponatraemia once desmopressin is started. Pituitary imaging and assessment of other anterior pituitary hormones are needed after the base-of-skull fracture.