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 tetrahydro aldosterone 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 tetrahydro aldosterone 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 tetrahydro aldosterone excretion. We included 625 participants in the analysis. The mean age was 47±14 years and 71% were male. The 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 tetrahydro aldosterone 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

FGF23 · Renin–angiotensin system · Aldosterone · Tetrahydroaldosterone · Steroid metabolite.

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Introduction

Cardiovascular complications are a major cause of the high morbidity and mortality in chronic kidney disease. Both cardiovascular and kidney disease have a broad spectrum of etiologies and clinical presentation, but during the progression of each disease, two hallmarks are an activation of the renin–angiotensin–aldosterone system (RAS), and a rise in serum concentrations of fibroblast growth factor 23 (FGF23) [1].

In patients with advanced heart failure, a direct association between plasma aldosterone and FGF23 was observed, but almost half of the patients were on aldosterone antagonists [2]. In larger and more recent studies, however, this observation could not be reproduced [3] [4]. Only indirect connections between RAS and FGF23 are available in these studies: hemodynamic intolerance of titrating RAS inhibitors up to target dosage was associated with higher FGF23 concentrations [4]. In hemodialysis patients, ultrafiltration volume as a surrogate for volume status positively associates with FGF23 concentrations [5].

We and others have previously shown in rodent models that salt depletion not only caused RAS activation but also increased circulating FGF23 [6, 7]. Vice versa, the treatment of rodents with FGF23 causes volume expansion and decreased serum and urinary aldosterone [8]. Pharmacological inhibition of excessive FGF23 in transgenic mice reverses the suppression of aldosterone [9]. These experimental results strongly support a direct link between RAS and FGF23.

We hypothesized that the difficulty to reproduce the reported association between aldosterone and FGF23 concentration in humans could arise from heterogeneity of the analyzed patient populations, a variability of the assays used [10], from the circadian rhythmicity of aldosterone secretion [11, 12], or a combination of the above.

Quantification of steroid hormones in timed urine collections allows sensitive determination of secreted hormone quantities over time [13]. Based on a well-characterized single-center registry of patients with kidney stones, we report that RAS activity surveyed by the urinary excretion rate of metabolite tetrahydro aldosterone [14] is independently associated with circulating FGF23.

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Materials and methods

1. Study population

The Bern Kidney Stone Registry (BKSR) is a single-center, observational cohort of kidney stone formers at the Department of Nephrology and Hypertension, Bern University Hospital, Bern, Switzerland. The BKSR adheres to the Declaration of Helsinki and was approved by the ethical committee of the Kanton of Bern (approval # BE 95/06). Inclusion criteria for the BKSR are (i) written informed consent, (ii) age≥18 years, and (iii) at least one past stone episode. All variables employed for study analyses were verified by a manual review of the original patient charts. In this study, we included BKSR participants who had urinary steroid profiles available and who had 24 h urine creatinine excretion that was within the 2.5th and 97.5th percentile of expected creatinine excretion [15]. Among the 1422 BKSR participants, 681 had a urinary steroid profile analysis available. Among these, 56 BKSR participants had 24 h urine creatinine excretion below the 2.5th or above the 97.5th percentile [15] and were excluded. Of the remaining 625 BKSR participants, 14 had no available urinary tetrahydro aldosterone analysis, and 297 had no measurement of FGF23. A final sample of 314 participants was included in the current study.

2. Data collection and measurements

Patients were instructed to collect two 24 h urine collections on a random outpatient diet and a spot urine and a fasting blood sample were obtained in the morning after the second of the 24 h urine collection. Plasma C-terminal FGF23 was measured at the laboratory of TECOmedical AG (Sissach, Switzerland) by the second-generation C-terminal assay (Immutopics, San Clemente, CA, USA) with plasma initially frozen after sampling and stored at−80 °C. C-terminal FGF23 was chosen due to its lower diurnal variability in comparison to intact FGF23 [16]. All other urine and blood parameters were analyzed at the Central Chemistry Laboratory of the Bern University Hospital directly after sampling, as described [17]. Assay characteristics for the measurements of FGF23, PTH, 25(OH)D, and 1,25(OH)2D were previously described [18]. The glomerular filtration rate (GFR) was estimated using the creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation [19]. Urinary creatinine excretion was used as the criterion for completeness of 24 h urine collections in a population with normal renal function [20, 21]. Percentiles 2.5 and 97.5 of 24 h creatinine excretion were calculated for each 24 h urine collection using linear regression [22]. Completeness of 24 h urine collections was assumed if the total 24 h creatinine excretion was within percentiles 2.5 and 97.5, and the 56 samples not within creatinine percentiles 2.5 and 97.5 were excluded. The mean value of both 24 h urine collections was used for the calculation of 24 h urinary excretion. Tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was calculated as previously described [23]. Diabetes was defined as the presence of reported or treated diabetes and/or fasting glycemia≥7 mmol/L (≥126.13 mg/dL). Hypertension was defined by the presence of any of the anti-hypertensive therapy prescribed, a mean systolic blood pressure≥140 mmHg, or a mean diastolic blood pressure≥90 mmHg.

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Quantification of urinary tetrahydro aldosterone by GC–MS

Urinary excretion of urinary tetrahydro aldosterone in μg/24 h was assessed in-house using an established GC–MS method as previously described [13, 24, 25]. Urine sample preparation consisted of pre-extraction on a Sep-Pak C18 column with a recovery standard medroxyprogesterone, followed by enzymatic hydrolysis using sulfatase and β-glucuronidase/arylsulfatase and extraction on Sep-Pak C18 cartridge. Steroids were derivatized using methoxyamine HCl 2% in pyridine at 60 °C for 1 h after adding Stigmasterol and 3β5β-TH-aldosterone standards, followed by derivatization with Tri-methyl-silyl imidazole (TMSI) at 100 °C for 16 h, and gel filtration on a Lipidex 5000 column. Samples were quantified using mass spectrometric analysis on a gas chromatograph 7890A coupled to a mass-selective Hewlett-Packard 5975C detector (both from Agilent Technologies, La Jolla, California, USA). Quality control of the method was ensured by comparison with parallel measurement of samples from healthy volunteers, and by monthly participation in external quality control as previously reported [25].

All statistical analyses were conducted using R software, version 4.0.4 (R Project for Statistical Computing, Vienna, Austria) [26]. The distribution of continuous variables was visually inspected. For C-terminal FGF23, in a univariable linear model with urinary tetrahydro aldosterone excretion, residuals were not normally distributed in assessment using the older package (SFig 1a–b). Therefore, C-terminal FGF23 underwent log transformation to improve distribution toward normality of residuals in statistical models. The statistical two-sample comparison was obtained using a two-sided Welch two-sample t-test, and p values<0.05 were considered statistically significant.

To assess the associations of log C-terminal FGF23 with urinary tetrahydro aldosterone, we computed a univariable linear model. This association of log C-terminal FGF23 with urinary tetrahydro aldosterone was further analyzed by eight multivariable linear models adjusting for sex, age, body mass index (BMI), eGFR (multivariable model 1), model 1 parameter, and parathyroid hormone, 25OH-vitamin D and 1.25(OH)2-vitamin D (multivariable model 2); model 1 parameters and 24 h sodium and potassium excretion (multivariable model 3). Multivariable linear model 4 was adjusted for model 1 parameters and seven classes of concurrently prescribed antihypertensive drugs (loop diuretics, thiazide diuretics, potassium-sparing diuretics, RAS inhibitors, alpha1 blockers, beta-blockers, and calcium antagonists. Four further multivariable models 1b to 4b were similarly calculated using the same set of parameters as before except including mGFR instead of eGFR.

Selected regression models were visualized using the visited package to show the entire model. Further, visited was used to display the effects of categorical subgroups and continuous predictor variables on the relationship between log C-terminal FGF23 and urinary tetrahydro aldosterone, while maintaining the effects of all other co-variables in the model constant [27].

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Discussion

In the present study, we found that the major urinary metabolite of aldosterone, tetrahydro aldosterone, quantified in 24 h urines by a sensitive and specific GC–MS assay [24] is positively associated with FGF23 concentrations in plasma of kidney stone formers. This association was robust about potential confounders. Our analyses provide a long-sought building block to strengthen a pathophysiological concept that integrates both RAS activation and excess in FGF23 as a common final stretch in heart and kidney disease [1].

by Imazu et al. [2] which is potentially biased by a wide use of aldosterone antagonists. It has furthermore been supported by a myocardial tissue analysis in human autopsies [38] and experimental data in rodents [6–9]. All further available data in humans are at best indirect hints [3–5] or use very limited patient numbers [39].

We confirm the earlier study by Imazu et al. in patients with heart failure patients and/or early kidney disease of whom 43% were prescribed aldosterone antagonists [2]. In that study, plasma aldosterone was positively associated with intact FGF23 concentrations irrespective of eGFR values [2]. In the present work, however, we investigated a different patient population, we used a different and much more sensitive aldosterone surrogate, and we employed a C-terminal FGF23 assay that is more robust for predicting adverse outcomes than intact FGF23 [40]. We also show the functional importance of our findings by displaying the negative association between urinary tetrahydro aldosterone and renal phosphate excretion using TmP/GFR. Another strength of the current study is the thorough assessment of the potential confounding effect of antihypertensive drug classes on the association between RAS activation and FGF23. We found no evidence that the observed effects are due to prescribed antihypertensive medications.

Further, our analyses demonstrate the suitability of the urinary metabolite tetrahydro aldosterone to assess clinical context or biomarkers associated with RAS activation. This has been previously suggested by others and even proposed as a screening tool for primary hyperaldosteronism [41]. For other steroid hormones also excreted in the urine, we have previously analyzed the current patient collective of kidney stone formers and have found associations of sex hormones with lithogenic factors, such as calcium, citrate, and oxalate excretion [17].

The present study has some limitations. Regarding the population studied, the present results are limited to stone formers. Stone formers constitute a somewhat heterogeneous population often exhibiting disadvantageous lifestyles and chronic diseases predisposing to stone formation with varying levels of kidney function.

Whether the association between aldosterone activation and plasma FGF23 exists beyond kidney stone formers remains to be validated, e.g., in populations of healthy volunteers and of patients with chronic kidney disease or congestive heart failure.

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Further, some variables, such as plasma renin activity or plasma aldosterone, were not available in the current study. However, results from a comparative study showed that urinary tetrahydro aldosterone excretion is the most reliable parameter to predict primary hyperaldosteronism [41]. Another limitation is the relatively small proportion of patients on diuretics, precluding us from safely estimating their potential effects on C-terminal FGF23 beyond the current dataset. Finally, by the nature of the cross-sectional study design, we were unable to assess clinical outcomes associated with excessive FGF23 and RAS activation.

In conclusion, our data reveal a robust association of RAS activity with circulating FGF23 in kidney stone formers. These findings are in line with previous studies in rodents and suggest a physiological link between the RAS system activation and FGF23 secretion.

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Matthias B. Moor1,2 Nasser A. Dhayat1,2 Simeon Schietzel1,2 Michael Grössl1,2 Bruno Vogt1,2 Daniel G. Fuster1,2

1 Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, Freiburgstrasse 15, 3010 Bern, Switzerland

2 Department of Biomedical Research, University of Bern, Bern, Switzerland