Diabetes Insipidus
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Direct answer
Passing more than 3 litres of persistently dilute urine daily — osmolality below about 300 mOsm/kg, specific gravity under 1.005 — with relentless thirst is diabetes insipidus, caused in central disease by vasopressin deficiency and in nephrogenic disease by renal resistance to it. The modern pathway is copeptin-based: a random basal copeptin of 21.4 pmol/L or more identifies nephrogenic DI outright, while a stimulated copeptin below about 4.9 pmol/L after hypertonic saline (or the classical water deprivation test with desmopressin response) indicates central disease. Central DI is treated with desmopressin; nephrogenic DI is treated by removing the cause — lithium, hypercalcaemia, hypokalaemia — with a thiazide (the paradoxical antidiuretic), amiloride for lithium cases, and salt-protein restriction as adjuncts.
What you must remember
- Numbers that define: urine volume over 3 L/day (up to 10–20 L in complete vasopressin absence), urine osmolality under 300 mOsm/kg, plasma sodium drifting toward the upper normal or frankly high when thirst access fails.
- Copeptin cut-offs: basal 21.4 pmol/L or more equals nephrogenic DI with near-perfect accuracy; below that, stimulated copeptin under roughly 4.9 pmol/L after hypertonic saline indicates central DI.
- Classical water deprivation test: deprive until urine osmolality plateaus (two consecutive samples within 10%) with plasma osmolality over 295 mOsm/kg, then give desmopressin 2 μg — urine osmolality rising over 50% means central DI, under 10% nephrogenic, with primary polydipsia already maximally concentrated and barely responding.
- Central causes: pituitary surgery (transsphenoidal), head trauma, craniopharyngioma, germinoma, Langerhans cell histiocytosis, and the familial AVP–neurophysin II defect — stalk thickening on MRI demands tumour workup in a young patient.
- Nephrogenic causes: lithium is the commonest (downregulates V2 receptors in the collecting duct), then hypercalcaemia, hypokalaemia, demeclocycline, post-obstructive uropathy, sickle cell disease, and the pregnancy-specific vasopressinase form.
- Treatment pairing: central — oral or intranasal desmopressin titrated to keep sodium 135–145 mmol/L, never to abolish thirst entirely; nephrogenic — thiazide with salt restriction, amiloride (blocks lithium entry through ENaC), NSAIDs, and correction of calcium and potassium.
- The triphasic response after pituitary surgery: transient DI for days 1–3, then SIADH from stored-hormone release around days 4–7, then permanent DI — mistaking phase two for cure leads to hyponatraemic disasters.
Six litres a day and a craving for ice water
A 35-year-old woman reports six months of polyuria, four-times-nightly nocturia and a specific craving for ice-cold water — a historically useful detail in true DI. Sodium is 146 mmol/L, urine osmolality 168 mOsm/kg. Basal copeptin is 3.2 pmol/L — well below 21.4, so nephrogenic disease is excluded without a dehydration test. She then undergoes water deprivation with hourly weights and osmolalities: urine osmolality plateaus at 210 mOsm/kg while plasma osmolality crosses 301, and after 2 μg of desmopressin her urine osmolality climbs to 480, far above the 50% rise that confirms central DI. MRI shows thickening of the pituitary stalk; germinoma markers and follow-up imaging are arranged — stalk disease in a young adult is histiocytosis or germinoma until proven otherwise. Desmopressin starts at bedtime to buy sleep, titrated against morning sodium. Education is the real prescription: weigh weekly (a 2 kg jump means water retention — skip a dose) and expect mild hyponatraemia when drinking is habit rather than thirst.
Where students slip
The costly error is treating primary polydipsia with desmopressin — the psychiatric patient who drinks litres suppresses vasopressin maximally, and adding hormone produces hyponatraemic seizures; the deprivation test exists to separate them, since the polydipsic patient concentrates urine reasonably well once deprived. The second slip is missing the lithium history, the hypercalcaemia or the hypokalaemia that makes nephrogenic DI reversible — a serum calcium and a drug list precede any stimulation test. Third, overcorrection with desmopressin: the sodium of 128 on Monday morning clinic is over-treatment, not disease, and the taught escape is a deliberate missed dose. Finally, the adipsic patient who feels no thirst runs dangerous hypernatraemia on a fixed schedule — worse than ordinary DI.
Frequently asked questions
When is a water deprivation test indicated, and what are its endpoints?
For confirmed hypotonic polyuria: deprive until urine osmolality plateaus on consecutive samples with plasma osmolality above 295 mOsm/kg, then administer desmopressin 2 μg and measure the response.
How does basal copeptin streamline the workup?
A random copeptin of 21.4 pmol/L or more diagnoses nephrogenic DI outright; lower values proceed to osmotic stimulation, where a value below about 4.9 pmol/L indicates central DI.
How is the desmopressin response interpreted at the end of a deprivation test?
A urine osmolality rise above 50% indicates central DI; a rise under 10% indicates nephrogenic DI; a modest or absent response from an already concentrated baseline suggests primary polydipsia.
Why does amiloride help lithium-induced nephrogenic DI?
Amiloride blocks the epithelial sodium channel through which lithium enters principal cells, reducing intracellular lithium that downregulates vasopressin V2 receptors and aquaporin-2 insertion.
What is the triphasic response after transsphenoidal surgery?
Transient DI (days 1–3) from posterior-lobe injury, then SIADH (around days 4–7) from release of stored hormone, then permanent DI if the hypothalamic neurons are destroyed.