Diabetes insipidus and polyuria-polydipsia — formative SAQs

SAQ 1 (10)

A 4-month-old boy is admitted for the third time with fever, vomiting, and poor feeding. He is irritable and dehydrated, and his weight has fallen across two centile lines. Serum sodium is 158 mmol/L, glucose is normal, and the urine is dilute (osmolality 120 mmol/kg) despite the dehydration. A maternal uncle had "kidney trouble as a baby." [3][9]

1. Give the most likely diagnosis, the pattern of inheritance, and the pathophysiological basis. (3) [9]
2. Outline how you would confirm the diagnosis and exclude the main alternatives. (3) [5][9]
3. Describe the long-term management and explain why early diagnosis matters. (4) [9][3]

Model answer

Diagnosis, inheritance, and pathophysiology. This is congenital nephrogenic diabetes insipidus (arginine vasopressin resistance). The picture — a young boy with recurrent fevers, vomiting, faltering growth, and hypernatraemia with inappropriately dilute urine, plus a maternally related affected male — points to the X-linked form from an AVPR2 mutation, which accounts for about 90 per cent of inherited cases. The V2 receptor on the collecting duct cannot respond to vasopressin, so aquaporin-2 is not inserted into the apical membrane, the kidney cannot concentrate urine, and free water is lost despite a high circulating vasopressin. [9]

Confirmation and alternatives. First exclude osmotic diuresis with the (normal) glucose. Confirm the water diuresis with paired serum and urine osmolality and a serum sodium — a high serum osmolality/sodium with a low urine osmolality is diagnostic of a concentrating defect. Distinguish nephrogenic from central disease by the response to desmopressin: in nephrogenic disease the urine does not concentrate, whereas central disease does. A high copeptin supports nephrogenic disease because vasopressin is present but ignored. Check calcium and potassium to exclude acquired nephrogenic causes, and take a family history for the X-linked pattern. Genetic testing (AVPR2, then AQP2) confirms the subtype. [5][9]

Long-term management and why early diagnosis matters. Desmopressin does not work in nephrogenic disease, so treatment reduces the solute the kidney must excrete and removes reversible factors. Provide a low-solute (low-sodium) diet with age-appropriate protein and free access to water, and use a thiazide diuretic with amiloride, adding indometacin to potentiate concentration. Early diagnosis matters because repeated hypernatraemic dehydration in infancy causes neurodevelopmental harm; recognising the pattern rather than repeatedly treating "sepsis" or "gastroenteritis" protects the developing brain and allows growth to be maintained. [9][3]

SAQ 2 (10)

A 9-year-old girl is referred with several months of thirst and passing large volumes of urine day and night, waking her from sleep. Random glucose is normal. Serum sodium is 144 mmol/L, serum osmolality 296 mmol/kg, and a random urine osmolality is 150 mmol/kg. She drinks about 5 litres a day and craves iced water. [5][10]

1. What is the syndrome, and what are the three diagnoses you must distinguish? (2) [10]
2. Describe how a copeptin-based approach separates the three, and how it improves on the water-deprivation test. (4) [5][7]
3. State the mechanism-based treatment for each of the three diagnoses and the key desmopressin safety rule. (4) [9][10]

Model answer

Syndrome and the three diagnoses. This is the polyuria-polydipsia syndrome (constant polyuria with polydipsia and a normal glucose, so a water diuresis). The three diagnoses to distinguish are central diabetes insipidus (arginine vasopressin deficiency), nephrogenic diabetes insipidus (arginine vasopressin resistance), and primary polydipsia. Her high-normal sodium and osmolality with dilute urine keep true diabetes insipidus firmly in view. [10]

Copeptin approach. Copeptin is the stable C-terminal fragment of the vasopressin precursor, released one-for-one with vasopressin, so it is a practical surrogate for vasopressin secretion. A high baseline copeptin (measured without prior fluid restriction) identifies nephrogenic disease, because vasopressin is present but the kidney ignores it. To separate central disease from primary polydipsia the copeptin is stimulated with hypertonic saline (to a target sodium, with close monitoring) or, more simply, with arginine: a stimulated copeptin that stays low indicates central disease, while an adequate rise indicates primary polydipsia. This improves on the water-deprivation test because that test performs poorly at separating partial central disease from primary polydipsia, where years of water loading blunt the medullary gradient and blur the result. [5][7]

Treatment by mechanism and the safety rule. Central disease is treated with desmopressin, titrated to control the polyuria. Nephrogenic disease is treated by removing reversible causes, a low-solute diet, free water, and a thiazide with amiloride and indometacin. Primary polydipsia is treated with fluid restriction and management of the behavioural or psychiatric driver — not desmopressin. The key safety rule is to allow a daily break in antidiuresis on desmopressin (and never to give it in primary polydipsia), because continued drinking under round-the-clock antidiuresis causes water retention, hyponatraemia, and hyponatraemic seizures. [9][10]