Thiazide-induced hyponatraemia: epidemiology and clues to pathogenesis

Thiazide diuretics are one of the most widely used and cost-effective classes of antihypertensive agents worldwide. Thiazides however have a significant side effect profile and are frequently insufficient to normalize blood pressure alone. Thiazide-induced hyponatraemia (TIH) is a major adverse effect, affecting up to one in seven patients receiving these drugs. TIH is more common in females, the elderly and those of low body weight and may cause symptoms such as confusion, falls and seizures. It is a common cause of hospital admission in the elderly. Although TIH occurs at least as frequently as hypokalaemia, much less is understood about the mechanism by which this occurs. Thiazides lower blood pressure by reducing the reabsorption of sodium from the distal nephron by inhibition of the NaCl cotransporter. The molecular mechanism by which this occurs together with the little known role of thiazides in regulating water reabsorbtion from the collecting ducts is discussed and the relevance to TIH evaluated. TIH is highly reproducible by thiazide rechallenge suggesting there may be a genetic predisposition. Both targeted resequencing of candidate genes and genome wide association techniques offer promising strategies by which such genetic contributions may be investigated. The rewards for uncovering the molecular mechanisms underlying TIH and the regulation of distal nephron sodium and water absorption are significant; not only could it inform the design of better tolerated, more efficacious thiazide-like antihypertensive agents but it may also facilitate the pharmacogenomic profiling of hypertensive patients to avoid thiazides in those likely to suffer adverse effects.