Urinary tetrahydroaldosterone is associated with circulating FGF23 in kidney stone formers

Abstract

The spectrum of diseases with overactive renin-angiotensin-aldosterone system (RAS) or elevated circulating FGF23 overlaps, but the relationship between aldosterone and FGF23 remains unclarified. Here, we report that systemic RAS activation sensitively assessed by urinary tetrahydroaldosterone excretion is associated with circulating C-terminal FGF23. We performed a retrospective analysis in the Bern Kidney Stone Registry, a single-center observational cohort of kidney stone formers. Urinary excretion of the main aldosterone metabolite tetrahydroaldosterone was measured by gas chromatography-mass spectrometry. Plasma FGF23 concentrations were measured using a C-terminal assay. Regression models were calculated to assess the association of plasma FGF23 with 24 h urinary tetrahydroaldosterone excretion. We included 625 participants in the analysis. Mean age was 47 ± 14 years and 71% were male. Mean estimated GFR was 94 ml/min per 1.73 m². In unadjusted analyses, we found a positive association between plasma FGF23 and 24 h urinary tetrahydroaldosterone excretion (β: 0.0027; p = 4.2 × 10^-7). In multivariable regression models adjusting for age, sex, body mass index and GFR, this association remained robust (β: 0.0022; p = 2.1 × 10^-5). Mineralotropic hormones, 24 h urinary sodium and potassium excretion as surrogates for sodium and potassium intake or antihypertensive drugs did not affect this association. Our data reveal a robust association of RAS activity with circulating FGF23 levels in kidney stone formers. These findings are in line with previous studies in rodents and suggest a physiological link between RAS system activation and FGF23 secretion.

Keywords: Aldosterone; FGF23; Renin–angiotensin system; Steroid metabolite; Tetrahydroaldosterone.

Fig. 1

Association of urinary tetrahydroaldosterone with plasma FGF23 in kidney stone formers. A and B display visualizations of a multivariable linear model in which urinary tetrahydroaldosterone (µg/24 h) associated with log-transformed FGF23 [log FGF23 RU/mL]. The model was adjusted for age, sex, eGFR and BMI. B depicts individual regression lines for each sex separately. Color-shaded areas indicate 95% confidence intervals

Fig. 2

Association of 24 h urinary sodium and potassium with 24 h urinary tetrahydroaldosterone excretion. Univariable association between urinary (A) sodium and B potassium excretion (mmol/24 h) and urinary excretion of tetrahydroaldosterone (µg/24 h). Gray shaded areas represent 95% confidence intervals