Читать книгу Disorders of Fluid and Electrolyte Metabolism - Группа авторов - Страница 40

Thiazide-induced hyponatremia (TIH) deserves a brief mention as its pathophysiology does not seem to fit any of the mechanisms described above. The traditional mechanism ascribed to TIH is that thiazides impair urinary dilution by inhibiting NCC. The diuretic effect of the drug also leads to mild volume contraction with activation of vasopressin. Thiazide-induced hypokalemia may play a role as well. However, it is well-known that patients with Gitelman syndrome do not typically present with hyponatremia despite having a genetic reduction of NCC activity [30]. Also, vasopressin might not play a role in TIH as thiazides have been shown to enhance water reabsorption in the inner medullary CD of Brattleboro rats, a strain of laboratory rats that lacks vasopressin [31]. Patients with TIH have also been found to have reduced or suppressed plasma levels of vasopressin [32, 33]. Recent literature point towards a genetic predisposition to TIH related to increased susceptibility to the action of prostaglandin E2 (PGE2) [33]. In a large cohort of patients with TIH, almost 50% carried a single nucleotide polymorphism in SLCO2A1, a gene encoding the prostaglandin transporter. The presence of this single nucleotide polymorphism manifests as a prostaglandin transporter with a reduced capacity to uptake luminal PGE2 in the CD as demonstrated by the presence of increased urinary excretion of PGE2 in these patients. PGE2 is known to increase AQP2 membrane trafficking mediated by the activation of apical prostaglandin receptor EP4 [34]. High luminal levels of PGE2 found on this cohort would lead to increased expression of AQP2, thereby increasing CD water permeability in the absence of vasopressin.