Clinical and Molecular Features of Thiazide-Induced Hyponatremia.

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.

Use of an educational, audiovisual podcast to maximise safety with variable rate intravenous insulin infusions.

Variable rate intravenous insulin infusions (VRIII) are used to maintain stable blood glucose in hospitalised patients with diabetes who are unable to eat or have a severe illness where good glycaemic control is paramount. With VRIII it is important to prescribe an adequate substrate to avoid hypoglycaemia and maintain electrolyte balance. Traditionally the substrate would have been varied to achieve this; current guidelines advise varying the infusion rate rather than the type of substrate. The local hospital Trust updated their VRIII prescription chart to reflect the Joint British Diabetes Societies' suggestions for inpatient care in October 2014. A local audit in January 2015 highlighted that 48% of patients on VRIII were prescribed the correct fluid as per the guideline. A questionnaire to assess prescriber knowledge regarding VRIII showed 40.4% of prescribers selected appropriate fluid for a patient with normal renal function and 11.5% of prescribers selected appropriate fluid for a patient with renal failure. An educational podcast was devised to explain the rationale behind appropriate fluid prescription with VRIII; this was shown to prescribers. Following the podcast, 75.8% of prescribers selected appropriate fluids for normal renal function and 54.5% for renal failure. Questionnaires were completed to assess prescriber knowledge prepodcast and postpodcast. Following the podcast, there was a significant increase in questionnaire scores, indicating improved prescriber knowledge surrounding VRIII. A reaudit of prescriptions for VRIII showed improvement in practice, where 63% of patients on VRIII were prescribed correct fluids. The use of a simple audiovisual podcast on VRIII led to a significant improvement in prescriber knowledge. Podcasts are an ideal medium to raise awareness around safety issues, including safe prescription of insulin. Further work will include the follow-up of participants to evaluate sustained knowledge and improvements of prescriptions in practice, with the overall aim of improving patient safety.

Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia.

Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone. GWAS in a separate cohort of 48 TIH patients and 2,922 controls from the 1958 British birth cohort identified an additional 14 regions associated with TIH. We identified a suggestive association with a variant in SLCO2A1, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro. These findings indicate that the phenotype of TIH involves a more extensive metabolic derangement than previously recognized. We propose one mechanism underlying TIH development in a subgroup of patients in which SLCO2A1 regulation is altered.

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.