Fibroblast growth factor 23: are we ready to use it in clinical practice?

Journal of Nephrology https://doi.org/10.1007/s40620-020-00715-2 REVIEW Fibroblast growth factor 23: are we ready to use it in clinical practice? Annet Bouma‑de Krijger1 · Marc G. Vervloet1 Received: 29 January 2020 / Accepted: 15 February 2020 © The Author(s) 2020 Abstract Patients with chronic kidney disease (CKD) have a greatly enhanced risk of cardiovascular morbidity and mortality. Over the past decade it has come clear that a disturbed calcium-phosphate metabolism, with Fibroblast Growth Factor-23 as a key hormone, is partly accountable for this enhanced risk. Numerous studies have been performed unravelling FGF23s actions and its association with clinical conditions. As FGF23 is strongly associated with adverse outcome it may be a promising biomarker for risk prediction or, even more important, targeting FGF23 may be a strategy to improve patient outcome. This review elaborates on the clinical usefulness of FGF23 measurement. Firstly it discusses the reliability of the FGF23 measurement. Secondly, it evaluates whether FGF23 measurement may lead to improved patient risk classification. Finally, and possibly most importantly, this review evaluates if lowering of FGF23 should be a target for therapy. For this, the review discusses the current evidence indicating that FGF23 may be in the causal pathway to cardiovascular pathology, provides an overview of strategies to lower FGF23 levels and discusses the current evidence concerning the benefit of lowering FGF23. Keywords FGF23 · Risk prediction · Cardiovascular disease · Clinical application Introduction Chronic kidney disease (CKD) is a major health concern, given its high prevalence and associated cardiovascular morbidity and mortality, leading to a high rate of health care consumption [1]. This high burden of cardiovascular disease (CVD) is seen in CKD stage 3 and beyond. Although traditional risk factors, such as hypertension, diabetes and smoking contribute to the development of CVD in CKD, they cannot fully explain the high incidence of cardiovascular mortality in these patients [2, 3]. Disturbances in calciumphosphate homeostasis are probably contributing to this high mortality risk [4]. A key hormone, in the regulation of calcium-phosphate homeostasis is the 32-kDa peptide Fibroblast Growth Factor-23 (FGF23). This hormone was discovered in the early 2000s in patients with autosomal dominant hypophosphataemic rickets (ADHR) [5]. This * Annet Bouma‑de Krijger Marc G. Vervloet 1 Department of Nephrology, Amsterdam Cardiovascular Science, Amsterdam University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands disease is characterized by hypophosphatemia and hyperphosphaturia resulting in growth retardation, bone deformities and rickets [6, 7]. FGF23 appeared to be the humoral factor to induce this excess renal phosphate loss. FGF23 is secreted by osteocytes in bone and is one of the three regulators of phosphate homeostasis, together with PTH and 1,25 dihydroxycholecalciferol (1,25(OH)2D3). The first two hormones both have phosphate lowering effects by decreasing tubular phosphate reabsorption by downregulation of the sodium dependent phosphate transporters (NaPi2a and NaPi2c) [8], but have opposite effects on vitamin D regulation, which is activated by PTH, but catabolized by FGF23 [9–12] (see Fig. 1). FGF23 acts on its main target organs, the kidney and parathyroid, by binding to the FGF23 receptors with α-Klotho as a co-receptor. This co-receptor is generally considered to be necessary to induce intracellular signal transduction, at least so for FGFR1 [13–15]. Nowadays FGF23 has gained wide attention in chronic kidney disease associated mineral bone disease (CKDMBD) and appears to be a candidate as missing link between chronic kidney disease and cardiovascular morbidity and mortality. FGF23 levels increase during progression of CKD [16, 17]. Although this, initially physiological, adaptation is crucial for maintaining phosphate balance in early CKD, prolonged exposure and extreme concentrations in advanced 13 Vol.:(0123456789) Journal of Nephrology Fig. 1  FGF23 physiology. Figure with permission adapted from Vervloet et al. Nature Reviews Nephrology 2017 (155) FGF23; Fibroblast growth factor 23, factor-23; Na-Pi-2a; Sodium-Phosphate co=transporter 2a CKD may have deleterious effects, in particular on the cardiovascular system [18–20]. Several observational studies showed an independent association between FGF23 levels and adverse outcome through all stages of CKD. Over the last decade a legion of studies has been published on FGF23, unravelling its biology, physiological actions and its association with clinical conditions. Some epidemiological data and experimental studies suggest that FGF23 not only acts as regulator of parathyroid hormone (PTH), vitamin D, or phosphorus, but may actually be in the causal pathway to cardiovascular pathology. However, definite proof of causality is lacking, since many questions still remain. This review will focus on the clinical usefulness of FGF23 as a biomarker and its potential use as a target for therapy. Reliability of FGF23 measurement Currently, FGF23 is rarely measured in routine clinical practice. There are four immunoassays commercially available for measurement of FGF23: Immutopics (1st and 2nd generation, San Clemente, USA), Kainos (Tokyo, Japan), Millipore (Billerica, USA) and DiaSorin (Saluggia, Italy). Most assays measure the intact 251 amino-acid protein (iFGF23) by simultaneous recognition of epitopes on the N- and C-terminal domains close to the proteolytic cleavage site. Additionally, Immutopics has an assay which measures both iFGF23 and the C-terminal fragment of FGF23 (cFGF23) by two antibodies against two epitopes within the C-terminal portion. 13 The four assays differ substantially as they are using different antibodies targeting different epitopes on the FGF23 protein. Besides different reported units [iFGF23 in picograms per milliliter (pg/ml) and cFGF23 in relative units (RU) per milliliter], absolute values between the assays vary substantially due to different calibration, and no harmonization has ever been conducted [21, 22]. If FGF23 would be used as a new biomarker certain issues need to be assessed. An ideal biomarker would be stable (no degradation ex vivo), show minimal diurnal variability and the analysis should be accurate, reproducible and affordable [23]. Stability of FGF23 There are several studies performed to assess the stability of FGF23, since intact FGF23 may be degraded by proteases or modified after blood withdrawal. First of all, iFGF23 is significantly more stable in plasma (EDTA) than in serum [24]. Even if samples after venepuncture are directly centrifuged and processed, there is the possibility of direct postvenepuncture instability of FGF23. The latter was investigated by Dirks et al. who found no differences between FGF23 concentrations in normal EDTA collecting tubes compared to (...truncated)