The impact of fibroblast growth factor-23 on the cardiovascular system in chronic kidney disease

Abstract

Chronic kidney disease is associated with an accelerated risk of cardiovascular (CV) mortality. Seminal work over the last decade has identified abnormal bone metabolism as an important modulator of the increased CV burden in this cohort. In particular, FGF23, a phosphaturic hormone with serum levels found to be markedly elevated in chronic kidney disease, is independently associated with increased risks of all-cause mortality and CV events. This editorial will discuss the proposed mechanisms linking FGF23 to CV disease in chronic kidney disease, namely, direct cardiac myocyte toxicity, endothelial dysfunction and vascular calcification.

Keywords:

• cardiovascular disease
• chronic kidney disease
• endothelial function
• fibroblast growth factor-23
• klotho
• left ventricular hypertrophy
• secondary hyperparathyroidism
• vascular calcification

Chronic kidney disease (CKD) is associated with a 10–20-fold increase in cardiovascular (CV) mortality and the absolute risk of death increases exponentially with increasing CKD stage [1,2]. Over the last decade, the overall cost of managing CKD per person per year has increased with multiple advances in therapeutic interventions, although patients with CKD are still left with an excessive CV disease (CVD) burden, compared to the general population [3]. CKD is a unique risk factor for CVD and broadly affects cardiac and vascular structure and function. The clinical consequences are endothelial dysfunction, increased vascular stiffness, accelerated atherosclerosis, left ventricular hypertrophy (LVH), valvular heart disease, and systolic and diastolic dysfunction [4]. The heightened CV risk in CKD can only be partially explained by the high prevalence of traditional CV risk factors, such as hypertension, diabetes mellitus, obesity, dyslipidemia, smoking and physical inactivity [5,6]. CKD-related risk factors, particularly abnormal bone mineral metabolism, are increasingly being found to amplify the mechanisms of CVD [7]. This narrative review will focus on a key aspect of abnormal bone mineral metabolism found to be associated with CVD in CKD, namely, FGF23.

FGF23 levels in CKD

FGF23 is a bone-derived phosphaturic hormone that is a central regulator of bone mineral homeostasis. Canonical FGF23 signaling requires membrane klotho, a co-receptor that improves the binding affinity of FGF23 to FGF receptors. The predominant actions of FGF23 are to increase renal phosphate excretion by downregulating proximal tubular luminal expression of sodium–phosphate co-transporters (NPT2a and c) and to inhibit synthesis of 1,25-dihydroxyvitamin D by downregulating renal 1α- hydroxylase and upregulating 24-hydroxylase [8,9]. In addition, FGF23 may also reduce the secretion of parathyroid hormone [10]. In animal models, administration of anti-FGF23 neutralizing antibodies to rats with CKD led to increased 1,25-dihydroxyvitamin D levels, increased serum calcium levels and reduced parathyroid hormone levels, suggesting that FGF23 inhibits vitamin D activation and contributes to secondary hyperparathyroidism [11].

In observational studies, FGF23 levels have been found to be elevated in both adult and pediatric CKD populations compared to healthy individuals. It is now evident that elevated serum FGF23 is an early marker of abnormal bone mineral metabolism in CKD that precedes other detectable abnormalities, such as phosphate, parathyroid hormone and vitamin D, and rises exponentially with deteriorating renal function [12]. Patients on dialysis may have levels up to 100–1000-fold above the upper reference limit for FGF23 [13]. Following kidney transplantation, FGF23 levels drastically fall and often return to normal by 1 year post transplantation [8].

FGF23 & CVD

Numerous studies have reported an association between FGF23 and the risks of mortality and CVD. Gutierrez et al. demonstrated that the highest quartile of C-terminal FGF23 was associated with a 5.7-fold increase in all-cause mortality in the first year following commencement of hemodialysis [14]. More recently, a meta-analysis of 14 prospective cohort studies found that a high FGF23 level (mix of C-terminal and intact assays) was independently associated with increased risks of all-cause mortality, CV events, CV mortality, stroke and heart failure [15]. However, due to the observational nature of all reported studies, it is not clear whether this association represents cause, consequence or confounding.

Several mechanisms have been proposed to explain the association between FGF23 and CVD, including direct myocardial injury, promotion of endothelial dysfunction and, possibly, development of vascular calcification (VC). However, high FGF23 levels may simply reflect hyperphosphatemia, which is associated with both VC and atherosclerosis [8]. In a rat model, neutralization of FGF23 with a monoclonal antibody led to increased mortality, which could be explained by the observed increase in serum phosphate [16].

The potential effect of FGF23 on myocardium has been evaluated in several animal models. Faul et al. demonstrated that wild-type mice developed LVH following intramyocardial or intravenous injections of FGF23 [17]. In addition, klotho-deficient mice were found to have higher FGF23 levels and LVH when compared to wild-type mice, suggesting a klotho-independent effect on cardiac myocytes. However, other studies have not equally shown the direct cardiotoxic effect of FGF23. Xie et al. found more severe LVH and cardiac fibrosis in klotho-deficient CKD mice compared to wild-type CKD mice, independent of serum phosphate and FGF23 levels [18]. Of interest, the differences in cardiac abnormalities were not observed among klotho-deficient and wild-type mice without CKD. Similarly, Agarwal et al. found no significant difference in left ventricular mass or ejection fraction in klotho-deficient mice compared to wild-type mice [19].

The plausible relationship between FGF23 and myocardial insult in humans was reported in the Chronic Renal Insufficiency Cohort (CRIC) study, where elevated C-terminal FGF23 levels were found to be independently associated with LVH in patients with CKD [17]. Another possible mechanism is FGF23-mediated upregulation of renal distal tubular sodium reabsorption, leading to volume expansion, hypertension and LVH. However, reverse causality may also explain this association. Patients in cardiogenic shock following myocardial infarction have been reported to have elevated C-terminal FGF23 levels, which were predictive of short- and long-term outcomes in the subgroup with renal impairment [20].

In addition to its cardiac effects, FGF23 may affect the vasculature directly. Klotho-deficient mice were found to have an attenuated arterial response to acetylcholine, in addition to reduced urinary nitric oxide (NO) metabolites, suggesting a relationship between FGF23 and vascular reactivity via the NO system [21]. Further evidence for this relationship was demonstrated in a recent study where infusion of exogenous FGF23 into mice led to inhibition of endothelium-dependent aortic vasodilatation in response to acetylcholine, also in association with a reduction in NO level. This inhibition was prevented by a superoxide scavenger, suggesting that FGF23 acts via superoxide to inhibit NO and cause vascular endothelial dysfunction [22].

Yilmaz et al. investigated this relationship between FGF23 and endothelial dysfunction in humans by assessing the effect of ischemia on forearm blood flow (flow-mediated dilatation) as a test of endothelial function [23]. They found a significant correlation between intact FGF23 levels and flow-mediated dilatation, which was partially attenuated by adjustment for serum levels of asymmetrical dimethyl arginine, a known endogenous inhibitor of NO synthase. This indicates the association between FGF23 and endothelial dysfunction may be mediated by asymmetrical dimethyl arginine.

The relationship between FGF23, atherosclerosis and VC has been explored in numerous recent studies, with conflicting results. Ozkok et al. found an association between serum intact FGF23 levels and progression of coronary artery calcification, measured by computed tomography, in 74 patients on hemodialysis [24]. This relationship was independent of the serum phosphate level. Similarly, a study of 55 peritoneal dialysis patients also found a correlation between intact FGF23 levels and VC on pelvic x-ray [25].

In contrast, the CRIC study investigators found no association between FGF23 and either the prevalence or severity of coronary artery calcification after multivariable adjustment in 1501 patients with CKD [26]. This apparent difference in results could be explained by the difference in the average renal function (end-stage renal failure vs CKD with average estimated glomerular filtration rate of 47 ml/min/1.73 m²) and the much larger sample size in the CRIC study. However, Moldovan et al. examined 88 hemodialysis patients and found no association between FGF23 and VC [27]. The group further reported that a higher serum FGF23 level was indeed protective against CVD, rather than being a risk factor. The CARE FOR HOMe study found the association between C-terminal FGF23 levels and incident atherosclerotic events was lost after adjustment for renal function and albuminuria, although FGF23 levels remained strongly associated with decompensated heart failure in patients with CKD stages 2–4 [28]. The current available literature supports a stronger association between FGF23 and both heart failure and LVH compared to atherosclerotic events.

Attempts to detect FGF23 within atherosclerotic lesions have also yielded conflicting results. In patients with normal renal function who underwent carotid endarterectomy for high-grade carotid stenosis, FGF23 has been identified in the atheromatous plaques [29]. In contrast, the CRIC study investigators were unable to identify FGF23 in calcified mouse aorta or vascular smooth muscle cells. They were also unable to induce VC experimentally in vitro [26].

Summary

Serum FGF23 levels are elevated early in the course of CKD and are associated with increased risks of both CVD and all-cause mortality. Although it remains uncertain whether this association is causal, FGF23 may contribute to CVD via direct cardiomyocyte effects (leading to LVH), endothelial dysfunction, VC and atherosclerosis through both klotho-dependent and -independent effects. Further studies are required to determine whether targeted intervention against FGF23 leads to improved CV outcomes in CKD patients.

Financial & competing interests disclosure

D Johnson is a consultant for Baxter Healthcare Pty Ltd and has previously received research funds from this company. D Johnson has also received speakers’ honoraria and research grants from Fresenius Medical Care and is a recipient of a Queensland Government Health Research Fellowship. C Hawley has received research funding from Baxter Healthcare Pty Ltd, Shire Pty Limited and Fresenius Medical Care. C Hawley has received travel grants from Amgen Australia. R Krishnasamy has received speaking honoraria from Shire Australia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.