Clinical and Molecular Features of Thiazide-Induced Hyponatremia

Abstract

Purpose of review: Hypertension affects more than 30% of the world's adult population and thiazide (and thiazide-like) diuretics are amongst the most widely used, effective, and least costly treatments available, with all-cause mortality benefits equivalent to angiotensin-converting enzyme inhibitors or calcium channel antagonists. A minority of patients develop thiazide-induced hyponatremia (TIH) and this is largely unpredictable at the point of thiazide prescription. In some cases, TIH can cause debilitating symptoms and require hospital admission. Although TIH affects only a minority of patients exposed to thiazides, the high prevalence of hypertension leads to TIH being the most common cause of drug-induced hyponatremia requiring hospital admission in the UK. This review examines current clinical and scientific understanding of TIH. Consideration is given to demographic associations, limitations of current electrolyte monitoring regimens, clinical presentation, the phenotype evident on routine clinical blood and urine tests as well as more extensive analyses of blood and urine in research settings, recent genetic associations with TIH, and thoughts on management of the condition.

Recent findings: Recent genetic and phenotyping analysis has suggested that prostaglandin E2 pathways in the collecting duct may have a role in the development of TIH in a subgroup of patients. Greater understanding of the molecular pathophysiology of TIH raises the prospect of pre-prescription TIH risk profiling and may offer novel insights into how TIH may be avoided, prevented and treated. The rising prevalence of hypertension and the widespread use of thiazides mean that further understanding of TIH will continue to be a pressing issue for patients, physicians, and scientists alike for the foreseeable future.

Keywords: Diuretics; Hypertension; Hyponatremia; TIH; Thiazide; Thiazide-induced hyponatremia.

Fig. 1

TIH can occur rapidly and is accompanied by excessive saliuresis [•]. Rechallenge of 11 patients with previous TIH (closed circles), young controls (open squares), and age-matched elderly controls (open circles) with a single oral dose of hydrochlorothiazide 50 mg plus amiloride 5 mg. Serum sodium fell within 6 h in TIH patients only (a) (*P < 0.01) and this was accompanied by excessive saliuresis relative to age matched controls (b) (**P < 0.01). Reproduced with permission from Eitan Friedman, MD, et al., Thiazide-Induced Hyponatremia: Reproducibility by Single Dose Rechallenge and an Analysis of Pathogenesis. Annals of Internal Medicine, Jan 01, 1989 110

Fig. 2

Hypothesis for the role of SLCO2A1 (also known as prostaglandin transporter, PGT) in contributing to thiazide-induced hyponatremia in individuals carrying the SLCO2A1 A396T variant. a Under low ADH conditions, apical PGT in the renal collecting duct scavenges PGE₂ from the lumen, resulting in aquaporin-2 (AQP2) internalization and minimal osmotic water reabsorption. b With reduced or absent apical PGT, PGE₂ reaching the lumen is able to stimulate apical EP4 receptors, resulting in insertion of AQP2 and osmotic water reabsorption [••]