The Effect of Thiazide Diuretics on Urinary Prostaglandin E2 Excretion and Serum Sodium in the General Population

Author:

Geurts Frank12ORCID,Rudolphi Crissy F1ORCID,Pelouto Anissa1ORCID,van der Burgh Anna C2ORCID,Salih Mahdi1ORCID,Imenez Silva Pedro Henrique1ORCID,Fenton Robert A3ORCID,Chaker Layal12ORCID,Hoorn Ewout J1ORCID

Affiliation:

1. Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center Rotterdam , 3000 CA Rotterdam , The Netherlands

2. Department of Epidemiology, Erasmus Medical Center, University Medical Center Rotterdam , 3000 CA Rotterdam , The Netherlands

3. Department of Biomedicine, Aarhus University , Aarhus DK-8000 , Denmark

Abstract

Abstract Context Thiazide-induced hyponatremia is one of the most common forms of hyponatremia, but its pathogenesis is incompletely understood. Recent clinical data suggest links with prostaglandin E2 (PGE2) and a single nucleotide polymorphism (SNP) in the prostaglandin transporter gene (SLCO2A1), but it is unknown if these findings also apply to the general population. Objective To study the associations between serum sodium, thiazide diuretics, urinary excretions of PGE2, and its metabolite (PGEM), and the rs34550074 SNP in SLCO2A1 in the general population. Design Prospective population-based cohort study (Rotterdam Study). Setting General population. Participants 2178 participants (65% female, age 64 ± 8 years) Intervention(s) None. Main Outcome Measure(s) Serum sodium levels. Results Higher urinary PGE2 excretion was associated with lower serum sodium: difference in serum sodium for each 2-fold higher PGE2 −0.19 mmol/L [95% confidence interval (CI) −0.31 to −0.06], PGEM −0.29 mmol/L (95% CI −0.41 to −0.17). This association was stronger in thiazide users (per 2-fold higher PGE2 −0.73 vs −0.12 mmol/L and PGEM −0.6 vs −0.25 mmol/L, P for interaction <.05 for both). A propensity score matching analysis of thiazide vs non-thiazide users yielded similar results. The SNP rs34550074 was not associated with lower serum sodium or higher urinary PGE2 or PGEM excretion in thiazide or non-thiazide users. Conclusion Serum sodium is lower in people with higher urinary PGE2 and PGEM excretion, and this association is stronger in thiazide users. This suggests that PGE2-mediated water reabsorption regulates serum sodium, which is relevant for the pathogenesis of hyponatremia in general and thiazide-induced hyponatremia specifically.

Funder

Dutch Kidney Foundation

Novo Nordisk Foundation

Publisher

The Endocrine Society

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