The Effect of FGF23 on Cardiac Hypertrophy Is Not Mediated by Systemic Renin-Angiotensin- Aldosterone System in Hemodialysis

Katharina Dörr, Michael Kammer, Roman Reindl-Schwaighofer, Matthias Lorenz, Rodrig Marculescu, Marko Poglitsch, Dietrich Beitzke, Rainer Oberbauer, Katharina Dörr, Michael Kammer, Roman Reindl-Schwaighofer, Matthias Lorenz, Rodrig Marculescu, Marko Poglitsch, Dietrich Beitzke, Rainer Oberbauer

Abstract

Fibroblast growth factor 23 (FGF23) is elevated in patients with chronic kidney disease and contributes to left ventricular hypertrophy (LVH). The aim of the analysis was to determine whether this effect is mediated by the renin-angiotensin-aldosterone system (RAAS) in hemodialysis. Serum samples from 62 randomized hemodialysis patients with LVH were analyzed for plasma renin activity (PRA-S), angiotensin II (AngII), and metabolites, angiotensin-converting enzyme-2 (ACE2) and aldosterone using a high throughput mass spectrometry assay. Compared to healthy individuals, levels of the RAAS parameters PRA-S, AngII and aldosterone were generally lower [median (IQR) PRA-S 130 (46-269) vs. 196 (98, 238) pmol/L; AngII 70 (28-157) vs. 137 (76, 201) pmol/L; Aldosterone 130 (54, 278) vs. 196 (98, 238) pmol/L]. We did not find an indication that the effect of FGF23 on LVH was mediated by RAAS parameters, with all estimated indirect effects virtually zero. Furthermore, FGF23 was not associated with RAAS parameter levels throughout the study. While there was a clear association between FGF23 levels and left ventricular mass index (LVMI) at the end of the study and in the FGF23 fold change and LVMI change analysis, no association between RAAS and LVMI was observed. Serum concentrations of PRA-S, AngII, and aldosterone were below the ranges measured in healthy controls suggesting that RAAS is not systemically activated in hemodialysis patients. The effect of FGF23 on LVMI was not mediated by systemic RAAS activity. These findings challenge the current paradigm of LVH progression and treatment with RAAS blockers in dialysis.

Clinical trial registration: [https://ichgcp.net/clinical-trials-registry/NCT03182699], identifier [NCT03182699].

Keywords: FGF23; chronic kidney disease; hemodialysis; left ventricular hypertrophy; renin-angiotensin-aldosterone-system.

Conflict of interest statement

RO reported grants from Amgen during the conduct of the study. In addition, RO, KD, and RR-S had a patent “Methods of treating left ventricle hypertrophy” pending. MP was employed by Attoquant Diagnostics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Dörr, Kammer, Reindl-Schwaighofer, Lorenz, Marculescu, Poglitsch, Beitzke and Oberbauer.

Figures

FIGURE 1
FIGURE 1
Hypothesis for the progression of left ventricular hypertrophy (LVH) due to FGF23 induced activation of the renin-angiotensin-aldosterone system (RAAS) cascade: FGF23 increases renin (indirectly by reducing the levels of active vitamin D). In addition, the levels of ACE2 are inhibited, increasing AngII and decreasing Ang(1-7), causing an increase in left ventricular mass.
FIGURE 2
FIGURE 2
FGF23 levels [upper panel (A)] and renin-angiotensin-aldosterone system (RAAS) levels [lower panel (B)] over the study period, stratified by study drug. In panel (A), the solid line was derived from a linear regression model for the log2 transformed FGF23 levels including measurement time as covariate. The shaded area depicts pointwise 95% confidence intervals for the predicted means at the given points in time. The diamonds and vertical bars at time 0 depict median and interquartile range for baseline FGF23 levels. The corresponding diamonds and vertical bars at later times summarize values from baseline to 3 months, from 3 to 6 months, and so on. In the panel (B) for RAAS levels depicted by boxplots, “Reference” refers to the RAAS values from a group of healthy male individuals, which were not part of this study, but are shown for comparison. Individual measurements are drawn as points.
FIGURE 3
FIGURE 3
Scatterplot of FGF23 levels and RAAS parameters stratified by the time of measurement (color) and study drug (shape). Changes of FGF23 were not associated with changes of RAAS parameters.
FIGURE 4
FIGURE 4
Scatterplot of renin-angiotensin-aldosterone system (RAAS) parameters and left ventricular mass index (LVMI), stratified by time of measurement (color) and study drug (shape). Changes of RAAS parameters were not associated with changes of LVMI.

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