Determinants of thiazide induced hyponatraemia in pre-exposed elderly–a controlled experiment

Background: Thiazide diuretics are widely used for the treatment of hypertension, they are effective, cheap and generally well tolerated. In elderly patients, hyponatremia frequently complicates the use of thiazide diuretics and, when severe, can lead to loss of consciousness, coma and even death. It cannot be predicted in who, or when, this serious complication will develop as the mechanisms resulting in thiazide-induced hyponatremia are unclear. Impaired free water excretion is thought to be primarily responsible for thiazide-induced hyponatremia. Decreased sensitivity of osmoreceptors, activating mutations in the ADH-receptor (AVPR2) or aquaporine-2 (AQP2) gene, decreased renal prostaglandin availability or impaired renal sodium handling as a result of mutations in thiazide- and amiloride-sensitive sodium channels may all be responsible for thiazide-induced hyponatremia. In the proposed trial we aim to elucidate the mechanisms underlying thiazide-induced hyponatremia and try to identify patients who are at risk of this potentially fatal complication by means of a controlled experimental study Hypothesis: Thiazide-induced hyponatremia is caused by impaired free water excretion either due to alterations in the ADH-AVPR2-AQP2 pathway or impaired renal sodium handling.
Patients and methods: a controlled experimental study comparing 18 elderly patients (aged 60-80 years) with previous thiazide-induced hyponatremia (sodium <125 mmol/l) and matched controls receiving a thiazide diuretic without hyponatremia. Before the experiment thiazides are stopped. During the experiment patients and controls receive a single dose of hydrochlorothiazide. Serum and urine sodium, serum ADH, urine AQP2 and prostaglandin E2 are determined to evaluate the response to hydrochlorothiazide. Urinary hydrochlorothiazide concentrations are measured to analyse differences in thiazide metabolism. Fluid balance will be monitored under ad libitum water drinking conditions. The response to ADH will be assessed by expression of AVPR2 in a cell-culture and determine its activity by measurement of cAMP.

Thiazide-induced hyponatremia is caused by impaired free water excretion either due to alterations in the ADH-AVPR2-AQP2 pathway or impaired renal sodium handling.

All subjects included in this controlled experiment will receive a single dose of Hydrochloorthiazide 50 mg. After that they will be monitored for 24hours