Lithium-induced nephrogenic diabetes insipidus on water deprivation testing

Electrolyte Disordersmedium

A 57-year-old man with diabetes and bipolar disorder treated for many years with lithium has 5 years of polyuria and polydipsia, worse over the past 3 months; he drinks 6 L daily. Medications are metformin and lithium. After a 12-hour fast (time 0), fasting continues for 6 more hours, with desmopressin given at 0, 2, and 4 hours. Values at 0, 2, 4, and 6 hours: serum sodium 148, 153, 155, 156 mEq/L; serum glucose 245, 204, 185, 201 mg/dL; urine sodium <30 mEq/L throughout; urine osmolality 90, 95, 97, 99 mOsm/kg H₂O. What is the most likely cause of his symptoms?

  1. A.Nephrogenic diabetes insipidusCorrect
  2. B.Central diabetes insipidus
  3. C.Primary polydipsia
  4. D.Glycosuria

Explanation

The most likely cause is nephrogenic diabetes insipidus due to long-term lithium therapy. After 12 hours of fasting, this patient is hypernatremic (serum sodium 148 mEq/L) with a urine osmolality of only 90 mOsm/kg, and with continued water deprivation and repeated desmopressin doses, serum sodium rises to 156 mEq/L while urine osmolality barely changes (99 mOsm/kg). A urine osmolality that remains below plasma osmolality despite hypernatremia and exogenous vasopressin defines nephrogenic diabetes insipidus. Lithium enters principal cells of the collecting duct through the epithelial sodium channel, inhibits glycogen synthase kinase 3-beta signaling, and reduces aquaporin-2 expression and trafficking, producing vasopressin resistance in up to 40% of long-term users. The defect can persist after lithium is stopped. Management includes coordinating with psychiatry about alternatives, amiloride to block lithium entry through ENaC, thiazide diuretics, and a low-solute diet. His worsening bipolar symptoms likely reflect falling lithium levels from adherence problems or altered handling, which should also be checked. Central diabetes insipidus also produces dilute urine with hypernatremia during water deprivation, but urine osmolality should rise by more than 50% (usually well above 300 mOsm/kg) after desmopressin. The absent response excludes it. Glycosuria causes osmotic diuresis, but solute diuresis produces urine osmolality near or above 300 mOsm/kg because glucose is the osmole being excreted. A urine osmolality of about 90 to 99 mOsm/kg is a water diuresis, and his glucose of 185 to 245 mg/dL is only modestly above the renal threshold. Primary polydipsia produces dilute urine because of excess intake, but serum sodium is usually low-normal and water deprivation leads to progressive urine concentration without hypernatremia. A rise in serum sodium to 156 mEq/L with persistently dilute urine is incompatible with primary polydipsia.

Why each option

A.
Correct. Hypernatremia to 156 mEq/L with urine osmolality under 100 mOsm/kg despite desmopressin indicates vasopressin resistance from chronic lithium therapy.
B.
Central diabetes insipidus responds to desmopressin with a rise in urine osmolality above 50%; urine osmolality here stays below 100 mOsm/kg.
C.
Primary polydipsia concentrates urine during water deprivation and causes low-normal sodium; rising serum sodium with persistently dilute urine excludes it.
D.
Glucose-driven osmotic diuresis yields urine osmolality near or above 300 mOsm/kg, not the 90 to 99 mOsm/kg water diuresis seen here.

Reference: Christ-Crain M, Nat Rev Dis Primers 2019 (diabetes insipidus); Batlle DC, N Engl J Med 1985 (amiloride in lithium-induced nephrogenic diabetes insipidus)

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