Abstract

Disturbances in mineral and bone metabolism in children with chronic kidney disease (CKD) lead to specific abnormalities of skeletal homeostasis called CKD–mineral and bone disorder (CKD-MBD). These disturbances should be diagnosed and managed appropriately to prevent bone deformities and disturbed growth. Changes in the vitamin D and parathyroid hormone (PTH), and the subsequent alterations in calcium (Ca) and phosphate (P) homeostasis are considered responsible for the development of CKD-MBD. Recently, a phosphaturic hormone, the fibroblast growth factor-23 (FGF-23), has been reported as a key regulator of P and vitamin D metabolism. A number of recent studies in paediatric populations have documented that the FGF-23 levels are increased early in CKD, before any abnormalities in serum Ca, P or PTH are apparent. The elevated FGF-23 levels result in a negative P balance to maintain P homeostasis, inducing phosphaturia, independently of PTH, and suppressing vitamin D synthesis. Therefore, the bone–kidney–parathyroid endocrine axis mediated by FGF-23 should be a novel therapeutic target in clinical practice, even in early stages of CKD in children.

Introduction

The article by Sinha et al. in this issue of Nephrology Dialysis Transplantation [1] draws attention to, and raises a number of interesting points about the relationship of fibroblast growth factor-23 (FGF-23) concentrations with declining renal function in paediatric patients with pre-dialysis chronic kidney disease (CKD).

It is well known that CKD causes disturbances in mineral and bone metabolism. These disturbances lead to specific abnormalities of skeletal homeostasis called CKD–mineral and bone disorder (CKD-MBD), which, if not treated appropriately during the critical phases of skeletal growth in children, can result in bone deformities and a disturbed growth [2]. Traditionally, the development of CKD-MBD has been ascribed to changes in the vitamin D and parathyroid hormone (PTH) endocrine system, and the subsequent alterations in calcium (Ca) and phosphate (P) homeostasis [3].

A recently described phosphaturic hormone, FGF-23, has been reported as a key regulator of P and vitamin D metabolism [4]. FGF-23 was first identified in patients with a distinct group of renal phosphate-wasting disorders: tumour-induced osteomalacia, autosomal dominant hypophosphataemic rickets and X-linked hypophosphataemic rickets [3]. Recent studies have demonstrated its importance in adults with CKD [5–7]. However, our understanding of the clinical significance of FGF-23 in paediatric patients with CKD who are at risk of developing CKD-MBD is still limited [1, 8–12].

Pathophysiological role of FGF-23 and Klotho in mineral metabolism

FGF-23, a 251-amino acid protein (molecular weight (MW) 26 kDa), is produced in osteoblasts and osteocytes in mineral bone [13], and requires the Klotho protein that binds to multiple FGF receptors and increases their affinity to FGF-23, thereby regulating FGF-23 signalling [4]. Klotho, named after a Greek goddess who spins the thread of life, is a multi-functional single-pass transmembrane protein that belongs to the family 1 glycosidases (MW 130-kDa) [14], and is expressed primarily in the renal tubules of the kidney and the choroid plexus in the brain [15].

FGF-23 and Klotho serve as major regulators of P homeostasis in both health and CKD. When P is in excess, FGF-23 is secreted from bone and acts on the kidney to induce phosphaturia, independently of PTH, and suppresses vitamin D synthesis, thereby inducing a negative P balance to maintain P homeostasis [16]. Studies in animals have shown that the phosphaturic action of FGF-23 is mediated by reducing the number of the electrogenic P contransporters [sodium-phosphate contransporter type-2a (NaP-2a)] and the electroneutral P contransporters [sodium-phosphate contransporter type-2c (NaP-2c)] on the brush border membrane of proximal tubules, thereby promoting renal P excretion [17, 18]. Moreover, FGF-23 suppresses synthesis of 1.25(OH)2D in proximal tubules by down-regulating the expression of the CYP27B1 gene, which encodes 1α-hydroxylase, the enzyme necessary for the synthesis of the active form of vitamin D [1.25(OH)2D] from its inactive precursor (25OHD). Furthermore, FGF-23 up-regulates expression of the CYP24 gene that encodes 24-hydroxylase, the enzyme that hydrolyzes and inactivates 1.25(OH)2D [16, 18]. The reduction in 1.25(OH)2D levels contributes to the decrease in P levels, since the P absorption from the intestine is decreased [19]. Furthermore, an experimental study has shown that FGF23 overexpression suppresses both osteoblast differentiation and matrix mineralization independently of its systemic effects on P homeostasis [20].

PTH also plays an important role in Ca and P homeostasis. PTH induces phosphaturia by reducing the abundance of the apical electrogenic P transporter, NaP-2a and NaP-2c contransporters on the brush border membrane of proximal tubules, thereby resulting in decreased luminal P transport [19]. Furthermore, it directly up-regulates expression of the gene, increasing 1α-hydroxylase activity and 1.25(OH)2D synthesis [21]. It is of interest that recent experimental and animal studies have identified the parathyroid gland as a target organ for FGF-23. The parathyroid gland expresses both Klotho protein endogenously and two FGF receptors. In fact, FGF-23 down-regulates PTH expression and suppresses PTH secretion both in vivo and in vitro [22].

The role of FGF-23 in CKD patients

Hyperphosphataemia, 1.25(OH)2D deficiency and secondary hyperparathyroidism are common findings in CKD patients. Recent studies have shown that the FGF-23 levels increase in CKD to maintain P homeostasis in the face of advancing renal insufficiency, both in pre-dialysis [5, 6] and dialysis adult patients [7]. Increased FGF-23 levels have been reported to be an independent predictor of progression of pre-dialysis CKD [6] and mortality in both haemodialysis [7] and transplant adult patients [23, 24], as well as an independent risk factor for allograft loss in kidney transplant recipients [23]. However, it is not clear if the association of increased FGF-23 levels and mortality in haemodialysis patients is just an association or a direct harmful effect of FGF-23 [19]. Very recently, elevated FGF-23 levels were found to be independently associated with left ventricular hypertrophy in a large CKD cohort. Animal studies demonstrated that FGF-23 had a Klotho-independent causal role in the pathogenesis of the left ventricular hypertrophy [25].

Why is FGF-23 increased in CKD patients?

The increased levels of FGF-23 in CKD patients is likely to be multi-factorial, including an increased production by bone in response to hyperphosphataemia due to decreased renal phosphate excretion [3, 19], and decreased FGF-23 renal clearance [19]. FGF-23 has been reported to increase early in adults with CKD, before any abnormalities in serum Ca, P or PTH are apparent, to maintain normal P levels in the face of declining nephron mass. However, FGF-23 worsens 1.25(OH)2D deficiency, directly inhibiting 1α-hydroxylase gene expression via activation of the extracellular signal-regulated kinase (ERK 1/2) signalling pathway [26], and thus contributes to the early pathogenesis of secondary hyperparathyroidism, before the development of serum mineral abnormalities [5]. An experimental study has shown that this process takes place in the early stages of CKD [27], and thus, the FGF-23/Klotho axis may contribute to some physiological stability in the early stages of CKD [28]. In advanced CKD, the hyperphosphataemia that is present may further contribute to decreased 1.25(OH)2D levels by inhibiting 1α-hydroxylase [3]. The low 1.25(OH)2D levels in turn result in reduced intestinal Ca absorption and low serum Ca levels. Hypocalcaemia, hyperphosphataemia and low 1.25(OH)2D levels stimulate PTH release from the parathyroid gland, leading to secondary hyperparathyroidism. Low 1.25(OH)2D levels are known to reduce the suppression of PTH gene transcription in the parathyroid gland, leading to secondary hyperparathyroidism. It is of interest that serum FGF-23 levels were found to be the most useful factor in predicting future development of refractory secondary hyperparathyroidism in long-term dialysis adult patients [29]. However, there is no scientific evidence to support the use of serum FGF-23 levels in clinical practice for the prevention of the development refractory secondary hyperparathyroidism in children with CKD.

Although calcitriol expression is suppressed by FGF23, conversely, activated vitamin D administration itself increases FGF-23 levels in both paediatric [30] and adult [31, 32] dialysis patients. Even though it is unclear whether this finding is mediated directly by the vitamin D analogue or indirectly due to alteration in serum Ca, P and PTH levels, a question arises as to whether the benefits of activated vitamin D use really outweigh the risks [33]. Most data agree that the use of activated vitamin D therapy in CKD patients with secondary hyperparathyroidism, and perhaps at low doses in the majority of patients with advanced CKD, represents an important therapeutic approach, despite the potential adverse effects of this therapy on FGF-23 levels [33].

FGF-23 in children with CKD

Published data on FGF-23 in paediatric populations with CKD are limited. In fact, there are seven published studies involving children with different stages of CKD [1, 8–12, 34], and three studies with paediatric renal transplant recipients [35–37].

Among these studies, two included paediatric patients on dialysis; 49 on peritoneal dialysis [8] and 16 on haemodialysis [11]. Both of these studies showed significantly elevated FGF-23 levels, associated with decreased osteoid thickness and shorter osteoid maturation time on bone biopsy [8], or with coronary artery calcification [11]. In fact, haemodialysis paediatric patients with coronary artery calcification had higher FGF-23 and P levels, compared with haemodialysis patients with no calcification [11].

There are four more studies that included various numbers (No 13–71) of paediatric patients with different stages of CKD (stage 1–5) [1, 9, 10, 12]. All the above studies have indicated a critical role of FGF-23 in CKD, as previously shown in adult and animal studies. In fact, they have shown that FGF-23 levels were significantly elevated early in CKD, with the higher levels found in CKD5. A positive correlation of FGF-23 levels with P and PTH levels, as well as a negative correlation with 1.25(OH)2D, estimated glomerular filtration rate (GFR) and tubular P re-absorption were also documented [9, 10, 12]. Furthermore, Magnusson et al. [10] investigated the development of bone mass and bone turnover over 2 years in relation to FGF-23 in 16 children with different stages of CKD. They found that, even though total bone mineral density was not correlated with FGF-23, the lumbar spine bone mineral density correlated with FGF-23 at baseline. Another study demonstrated that skeletal FGF-23 expression was increased in 32 patients aged 2–26 years, with CKD2–4 or on dialysis, and was related to skeletal mineralization, suggesting that osteocyte function is altered early in the course of CKD [34].

Three recent studies have investigated the role of FGF-23 in paediatric renal recipients, and they have shown an inverse correlation of GFR with FGF-23 among renal recipients with CKD [35–37]. Moreover, FGF-23 levels were found to be associated with increased risk of deterioration of kidney function and episodes of rejection [36].

The study by Sinha et al. [1] is of particular importance, because it included a considerably larger number of non-dialysed CKD3–5 children with a more balanced GFR distribution. These patients had careful clinical management for prevention of CKD-MBD and received on time oral phosphate binders and/or orally active vitamin D compounds. This management allowed the potential confounding effects of PTH and P elevation with declining GFR to be removed. Therefore, the relationship of FGF-23 and GFR of these patients became more evident. However, despite this careful management, 21% of the patients had PTH values more than double the upper limit of normal. Hopefully, in the future, this percentage will be decreased with an early referral of these patients and the restriction of their phosphate intake.

The necessity for higher FGF-23 levels early in CKD than in normal population to maintain normal serum P levels, demonstrated by the majority of studies in children [1, 9, 10, 12], may represent a compensation for end-organ resistance to FGF-23 as a result of decreased Klotho expression in the kidney. Klotho expression is up-regulated by 1.25(OH)2D and down-regulated by elevated FGF-23 levels. However, it remains to be determined whether decreased Klotho expression is one of the earliest findings in the progression of CKD [16].

In conclusion, FGF-23 seems to be a new ‘player’ in the axis of CKD-MBD, in addition to the traditionally well-known ‘players’, namely Ca, P and PTH-vitamin D endocrine system. Except for the well-established regulatory effects of FGF-23 on bone and mineral metabolism, its cardiovascular effects have also received much attention. Therefore, FGF-23 might be a promising new therapeutic target that might improve CKD-MBD. However, further studies regarding the use of FGF-23 concentrations in clinical practice of CKD-MBD management in children are necessary to draw definitive conclusions.

Conflict of interest statement

The authors confirm that we have no conflicts of interest to declare. We declare that the results presented in this paper have not been published previously in whole or part, or in abstract format.

(See related article by Sinha et al. Investigating FGF-23 concentrations and its relationship with declining renal function in paediatric patients with pre-dialysis CKD Stages 3–5. Nephrol Dial Transplant 2012; 27: 4361–4368.)

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