Abstract Three members of the fibroblast growth factor (FGF) family, FGF19, FGF21 and FGF23, are different from the other members in two major aspects. First, they are actually not growth factors but endocrine factors that regulate various metabolic processes. Second, their physiological receptors are not FGF receptors (FGFRs) but binary complexes of FGFRs and Klotho proteins. FGF23 and FGF21 have emerged as biomarkers that start increasing in early-stage chronic kidney disease (CKD). FGF23 is a bone-derived phosphaturic hormone that binds to the αKlotho–FGFR complex expressed in renal tubules to increase phosphate excretion per nephron. The FGF23 increase is deemed necessary to compensate for the decrease in the nephron number during CKD progression and to maintain the phosphate balance. However, the increase in phosphate excretion per nephron induces renal tubular damage and accelerates nephron loss. CKD progression is also associated with an increase in calciprotein particles (CPPs) in the blood. CPPs are calcium–phosphate nanoparticles with the ability to induce endothelial damage and inflammatory responses. The fact that serum CPP levels are correlated with vascular calcification/stiffness and mortality in CKD patients suggests that CPPs may serve as a ‘pathogen’ of cardiovascular complications. Like FGF23, FGF21 starts increasing in early-stage CKD. FGF21 is a liver-derived hormone that binds to the βKlotho–FGFR complex expressed in the central nervous system to induce stress responses, including activation of the sympathetic nervous system and the hypothalamus–pituitary–adrenal axis. Thus FGF21 and FGF23 are not merely biomarkers for CKD progression but potential pathogenic agents that accelerate CKD progression and aggravate cardiovascular complications. calciprotein particles, FGF-21, FGF-23, Klotho, PTH, vitamin D INTRODUCTION Founding members of the fibroblast growth factor (FGF) family, FGF1 and FGF2 (also known as acidic FGF and basic FGF, respectively), were originally identified as mitogens promoting proliferation of fibroblasts and vascular endothelial cells [1, 2]. The promiscuous mitogenic activity in mesenchymal cells contributes to regulation of multiple biological processes in various stages of life, including morphogenesis in embryonic development, wound healing and angiogenesis . FGF1 and FGF2 bind to the FGF receptor (FGFR) family of tyrosine kinases and function primarily in an autocrine or paracrine manner. This mode of action is likely attributed to the fact that these FGFs have heparin-binding domains, through which they tether themselves to heparan sulfate (HS) in the extracellular matrices . Of note, HS is indispensable for formation of the FGF–FGFR–HS ternary complex, which is required for FGF to activate the FGFR . Unlike FGF1 and FGF2, three members of the FGF family, FGF19 (the human ortholog of FGF15 in rodents), FGF21 and FGF23, lack heparin-binding domains and thus have low affinity to HS, which enables them to diffuse away from the extracellular matrices, enter the bloodstream and function in an endocrine manner . However, lack of heparin-binding domains precludes endocrine FGFs from formation of the FGF–FGFR–HS ternary complex and activation of FGFR in their target organs. This problem has been solved by evolution of the Klotho gene family encoding single-pass transmembrane proteins [6, 7]. Specifically, αKlotho protein forms a binary complex with FGFR1c constitutively to create a groove into which FGF23 fits, thereby facilitating formation of the FGF23–FGFR1c–αKlotho ternary complex and activation of FGFR  (Figure 1). Similarly, βKlotho protein forms a binary complex with FGFR1c or FGFR4 and is required for FGF21 or FGF15/19, respectively, to form the ternary complexes and activate the FGFRs [9–12]. Thus expression of both Klothos and specific FGFR isoforms in the right combination are the prerequisite for target organs of endocrine FGFs . FIGURE 1: View largeDownload slide Crystal structure of the FGF23–FGFR1c–αKlotho complex (from ). The N-terminal region of FGF23 (orange) interacts with the extracellular D2 (green) and D3 (purple) domains of FGFR1c, whereas the C-terminal region of FGF23 (red) interacts with αKlotho. αKlotho is composed of the KL1 (cyan) and KL2 (blue) domains, which have homology to family 1 glycosidases. The KL2 domain has a receptor binding arm (RBA) that captures FGFR1c. KL: Klotho. Reprint by permission from Springer Customer Service Centre GmbH: Springer Nature, Nature, α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling, Gaozhi Chen, Yang Liu, Regina Goetz, Lili Fu, Seetharaman Jayaraman et al., Macmillan Publishers Limited, part of Springer Nature, 2018. FIGURE 1: View largeDownload slide Crystal structure of the FGF23–FGFR1c–αKlotho complex (from ). The N-terminal region of FGF23 (orange) interacts with the extracellular D2 (green) and D3 (purple) domains of FGFR1c, whereas the C-terminal region of FGF23 (red) interacts with αKlotho. αKlotho is composed of the KL1 (cyan) and KL2 (blue) domains, which have homology to family 1 glycosidases. The KL2 domain has a receptor binding arm (RBA) that captures FGFR1c. KL: Klotho. Reprint by permission from Springer Customer Service Centre GmbH: Springer Nature, Nature, α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling, Gaozhi Chen, Yang Liu, Regina Goetz, Lili Fu, Seetharaman Jayaraman et al., Macmillan Publishers Limited, part of Springer Nature, 2018. PHYSIOLOGY OF THE FGF23–αKLOTHO ENDOCRINE AXIS αKlotho is expressed in a tissue-specific manner, predominantly in distal convoluted tubules in the kidney, epithelial cells in the choroid plexus and chief cells in the parathyroid gland [6, 14]. These cells also express FGFR1c, FGFR3c and/or FGFR4 , which are capable of forming binary complexes with αKlotho , and thus are considered targets of FGF23. In fact, when FGF23 acts on the FGFR–αKlotho complex in distal tubules , it suppresses reabsorption of phosphate and activation of vitamin D in proximal tubules . Namely, FGF23 functions as a phosphaturic hormone and as a counter-regulatory hormone for 1,25-dihydroxyvitamin D3 (calcitriol) . However, it remains elusive how FGF23 that acts on distal tubules regulates proximal tubular function . It also remains elusive how osteocytes and/or osteoblasts sense phosphate and regulate FGF23 secretion/production to balance the dietary phosphate intake with urinary phosphate excretion. The simplest hypothesis would be that osteocytes/osteoblasts secrete FGF23 when a putative phosphate-sensing receptor perceives an increase in the blood phosphate level. However, the mechanism appears not so simple, because several animal studies have indicated that FGF23 increases not only with serum phosphate but also with serum calcium  and that FGF23 failed to increase with serum phosphate or calcium in the presence of hypocalcemia or hypophosphatemia, respectively . These findings indicate that both phosphate and calcium are necessary for appropriate regulation of FGF23. When FGF23 acts on the parathyroid gland, it suppresses secretion and synthesis of parathyroid hormone (PTH) . Conversely, PTH increases FGF23 directly by acting on osteocytes/osteoblasts  and indirectly by increasing calcitriol, because FGF23 is a target gene of calcitriol . It is also possible that PTH may increase FGF23 indirectly by raising serum calcium. Thus three hormones that control mineral metabolism, PTH, calcitriol and FGF23 are interconnected to each other with three negative feedback loops  (Figure 2). FIGURE 2: View largeDownload slide Negative feedback loops between hormones that regulate mineral metabolism. αKlotho is expressed in the parathyroid gland and the kidney. FGF23 lowers PTH and 1,25-dihydroxyvitamin D3 (vitamin D), whereas PTH and 1,25-dihydroxyvitamin D3 increase FGF23. FIGURE 2: View largeDownload slide Negative feedback loops between hormones that regulate mineral metabolism. αKlotho is expressed in the parathyroid gland and the kidney. FGF23 lowers PTH and 1,25-dihydroxyvitamin D3 (vitamin D), whereas PTH and 1,25-dihydroxyvitamin D3 increase FGF23. THE FGF23–αKLOTHO ENDOCRINE AXIS IN CHRONIC KIDNEY DISEASE Chronic kidney disease (CKD) results from various causes, including diabetes, hypertension, chronic glomerulonephritis and polycystic kidney disease among others. Regardless of the cause, a common clinical picture universally observed during CKD progression is deemed a gradual decrease in the functional nephron number, which also occurs as a consequence of natural aging . The decrease in the nephron number should activate the FGF23–αKlotho endocrine axis . Unless dietary phosphate intake is reduced, phosphate excretion per nephron must be increased accordingly to maintain the phosphate balance. This demand is met by increasing FGF23. The increase in FGF23 is supposed to lower calcitriol and the decrease in calcitriol should be followed by an increase in PTH. In fact, clinical studies have confirmed that an increase in FGF23, decrease in calcitriol, and increase in PTH occur in this order during CKD progression . Serum phosphate is the last to increase . Hyperphosphatemia ensues in end-stage renal disease, when the residual nephron number is reduced to a level incapable of excreting the ingested phosphate into urine (Figure 3). FIGURE 3: View largeDownload slide Changes in serum levels of FGF23, PTH, 1,25-dihydroxyvitamin D3 (vitamin D) and phosphate during CKD progression. An increase in FGF23 is the earliest change. A decrease in 1,25-dihydroxyvitamin D3 and then an increase in PTH ensues in this order. Phosphate is the last to increase. FIGURE 3: View largeDownload slide Changes in serum levels of FGF23, PTH, 1,25-dihydroxyvitamin D3 (vitamin D) and phosphate during CKD progression. An increase in FGF23 is the earliest change. A decrease in 1,25-dihydroxyvitamin D3 and then an increase in PTH ensues in this order. Phosphate is the last to increase. Besides FGF23, PTH has phosphaturic activity and can increase phosphate excretion per nephron. However, the fact that the FGF23 increase precedes the PTH increase during CKD progression suggests that FGF23, but not PTH, is primarily responsible for maintaining the phosphate balance in CKD. It also suggests that the PTH increase is a result of the calcitriol decrease caused by the FGF23 increase. This notion has been verified in CKD rats exhibiting high FGF23, low calcitriol and high PTH . They had high fractional excretion of phosphate (FEP), a surrogate of phosphate excretion per nephron, but their serum phosphate levels were within normal range, representing a model for early-stage CKD. When these CKD rats were administered with a neutralizing antibody against FGF23, a decrease in FEP, increase in serum phosphate and increase in calcitriol were observed within 24 h. However, PTH remained high until 48 h after the antibody treatment, indicating again that FGF23, but not PTH, is primarily responsible for maintaining the phosphate balance. Thus the adaptive response of the FGF23–αKlotho endocrine axis is required for phosphate homeostasis, at least in early-stage CKD. However, ironically, this adaptation may accelerate CKD progression. It has been known since 1980s that an increase in phosphate excretion per nephron induces renal tubular damage and interstitial fibrosis in rats . Haut et al.  manipulated phosphate excretion per nephron by placing partially nephrectomized rats on a diet containing different amounts of phosphate for 18 weeks and then scored the histological kidney damage. Their conclusion was that the severity of renal tubular damage and interstitial fibrosis was positively correlated with phosphate excretion per nephron. A plausible mechanism was that an increase in phosphate excretion per nephron could increase the phosphate concentration of the renal tubular fluid, which likely exceeded the solubility limit and triggered precipitation of calcium–phosphate (CaPi) in the lumen . CaPi nanocrystals were reported to induce cellular damage when applied to cultured renal proximal tubular cells through a mechanism yet to be identified . Persistent CaPi-induced renal tubular damage can result in interstitial fibrosis and eventually decrease the nephron number, which may further increase phosphate excretion per nephron and thus promote CaPi precipitation unless phosphate intake is reduced, thereby triggering a vicious cycle leading to progressive nephron loss. This hypothetical mechanism is supported by the fact that the kidney damage induced by a high-phosphate diet in rats was alleviated by administration of bisphosphonate, which can prevent formation of CaPi crystals . Although the FGF23–αKlotho endocrine axis had not been discovered at that time, if FGF23 had been measured in this study, FGF23 would have been positively correlated with the histological kidney damage. Provided that the FGF23 increase in CKD patients is a sign of excess phosphate intake relative to the residual nephron number, it can be a reason for phosphate restriction, even when serum phosphate levels are within normal range. The FGF23 increase may also be regarded as a risk for renal tubular damage and interstitial fibrosis . This notion needs to be verified in future clinical studies. CALCIPROTEIN PARTICLES Since hyperphosphatemia was identified as a risk for vascular calcification and increased mortality in CKD patients, phosphate binders have been used to lower serum phosphate levels and indeed improved clinical outcomes . However, vascular calcification and increased mortality are frequently observed in CKD patients  whose serum phosphate levels are within normal range, suggesting that a factor(s) other than phosphate per se may contribute to cardiovascular complications. Recent clinical studies have identified calciprotein particles (CPPs) as a novel biomarker associated with coronary artery calcification, vascular stiffness and chronic inflammation in CKD patients [33, 34]. CPPs are defined as aggregates of serum proteins (mainly fetuin-A) laden with tiny CaPi precipitates, which are dispersed in the blood as colloids [30, 35–37] (Figure 4). Fetuin-A is one of the most abundant serum proteins produced in the liver and secreted into the blood. Fetuin-A has enormous capacity for absorbing CaPi precipitates and is indispensable for preventing CaPi from being precipitated in the extraosseous tissues. In fact, mice lacking fetuin-A suffer from vast ectopic calcification . However, CPPs induce cell death in vascular endothelial cells, calcification in vascular smooth muscle cells and innate immune responses in macrophages in culture [39–43]. These findings have raised the possibility that CPPs may not merely serve as a biomarker but function as a pathogen responsible for vascular calcification and increased mortality in CKD patients [30, 44]. FIGURE 4: View largeDownload slide Formation of CPPs. CaPi is absorbed by serum protein fetuin-A and prevented from growing into large precipitates in the blood. As a result, aggregates of CaPi-laden fetuin-A (CPP) are generated and dispersed in the blood as colloids. FIGURE 4: View largeDownload slide Formation of CPPs. CaPi is absorbed by serum protein fetuin-A and prevented from growing into large precipitates in the blood. As a result, aggregates of CaPi-laden fetuin-A (CPP) are generated and dispersed in the blood as colloids. In the previous clinical studies, serum CPP levels were indirectly measured by calculating the difference in serum fetuin-A levels before and after centrifugation of the serum sample at 16 000∼24 000 g for 2 h, which is believed to precipitate CPPs [33, 34]. However, this assay has two major limitations. First, the lower the CPP levels, the less accurate the assay, especially when the reduction rate of serum fetuin-A levels after the centrifugation is close to the coefficient of variation of the fetuin-A assay kit. Second, low-density CPPs that are never precipitated by centrifugation, if any, are impossible to measure. To overcome these limitations, we have developed a novel assay for quantification of plasma CPPs using a fluorescent probe that specifically binds to calcium–phosphate crystals . Using this novel assay, we measured plasma CPP levels and other clinical parameters relevant to mineral metabolism in 148 nondialysis CKD patients and identified serum phosphate and age as independent determinants of the plasma CPP level . It should be noted that serum phosphate levels were within normal range in the majority of patients in this study, indicating that plasma CPP levels were positively correlated with serum phosphate levels even among normophosphatemic patients. It was previously reported that an increase in serum phosphate levels, even within normal range, is independently associated with a higher cardiovascular event rate and all-cause mortality . Taken together, it is intriguing to speculate that vascular calcification and increased mortality in CKD patients without hyperphosphatemia can be explained by increased CPPs. CPPs are not uniform but highly variable in particle size, density and composition . It is of critical importance to clarify the relation between physicochemical properties and biological activity of CPPs in future research. FGF23 IN THE REGULATION OF SODIUM Because FGF23 is increased with CKD progression , and because CKD progression is associated with increased vascular calcification , one would expect a positive correlation between FGF23 and vascular calcification. Unexpectedly, FGF23 is associated not with arterial calcification , but with congestive heart failure (CHF), left ventricular hypertrophy, (LVH) and atrial fibrillation (AF) [49, 50]. These associations may be attributed to the effect of FGF23 on renal sodium handling. Besides suppressing phosphate resorption in proximal tubules by downregulating sodium-dependent phosphate cotransporter type IIa/c (Npt2a/c) , FGF23 was recently reported to upregulate sodium chloride cotransporter (NCC) in distal tubules to promote sodium resorption . FGF23 increases the expression and membrane abundance of NCC directly by activating the canonical FGF signaling pathway through binding to the FGFR–αKlotho complex in distal tubules. Thus FGF23 functions not only as a phosphaturic hormone but also as a sodium-conserving hormone. The ability of FGF23 to induce sodium retention may explain why FGF23 is associated with CHF in CKD patients. It may also contribute to LVH indirectly through inducing volume expansion, in parallel with the direct effect of supraphysiological levels of FGF23 on cardiomyocytes that induces hypertrophy in an αKlotho-independent manner . In addition, mutual activation of the FGF23–αKlotho endocrine axis and the renin–angiotensin–aldosterone system (RAAS) may occur in CKD. Namely, FGF23 may activate RAAS, because it has been reported in animal studies that FGF23 downregulates αKlotho  and that a decrease in αKlotho causes an increase in plasma aldosterone levels . Conversely, aldosterone induces FGF23 expression directly in cultured osteoblastic cells . Activation of the RAAS is known to contribute to cardiac hypertrophy, fibrosis and remodeling , which may result in an increased incidence of AF, although the precise mechanism remains elusive. In addition, the physiological significance of the fact that FGF23 is bestowed with both phosphate-wasting and sodium-conserving activity simultaneously remains to be determined. PHYSIOLOGY OF THE FGF21–βKLOTHO ENDOCRINE AXIS FGF21 was originally identified as a glucose-lowering hormone in an effort to search for novel proteins with a therapeutic potential for diabetes . The initial view on the mode of FGF21 action was that FGF21 was secreted from the liver upon fasting to induce metabolic adaptation for fasting. Specifically, transgenic mice forced to express FGF21 in the liver (FGF21 transgenic mice) and/or mice injected with recombinant FGF21 exhibit increased lipolysis in white adipose tissue (WAT), increased ketogenesis, gluconeogenesis and fatty acid oxidation in the liver . FGF21 binds to the FGFR1c–βKlotho complex to activate the canonical FGF signaling pathway . Although both WAT and liver express βKlotho, FGF1c is expressed predominantly in WAT but barely in the liver . Thus the liver is not a primary target organ of FGF21. Instead of FGFR1c, the liver mainly expresses FGFR4, which also forms binary complexes with βKlotho to serve as the high-affinity receptor for FGF15/19 . Thus the metabolic effects of FGF21 on the liver are considered secondary to those on the primary target organs. Subsequently FGF21 was shown to cross the blood–brain barrier and act directly on the suprachiasmatic nucleus (SCN) where both βKlotho and FGFR1c are expressed . Activation of the SCN neurons by FGF21 increases corticotropin-releasing hormone (CRH), which activates the hypothalamus–pituitary–adrenal (HPA) system to increase glucocorticoid levels in the peripheral blood. CRH also activates the sympathetic nervous system, which promotes lipolysis . These responses induced by FGF21 are, in a word, stress responses. Because FGF21 induces metabolic responses to fasting, FGF21 transgenic mice exhibit a metabolic state as if they were starved or calorie-restricted even when they are actually fed . In addition, FGF21 transgenic mice are supposed to have enhanced responses to stress. Of note, metabolic responses to caloric restriction and improved stress responses are associated with extended lifespan in various species . In fact, FGF21 transgenic mice live significantly longer than wild-type mice , indicating that FGF21 functions as an antiaging hormone. THE FGF21–βKLOTHO ENDOCRINE AXIS IN CKD Multiple clinical studies have shown that FGF21 is increased progressively with a decline of renal function . Furthermore, high FGF21 levels predict high all-cause mortality in end-stage renal disease patients . The fact that higher levels of an antiaging hormone (FGF21) predicts higher mortality appears seemingly paradoxical; however, it is possible to interpret that higher FGF21 is a survival response against greater ‘stress’ due to more severe clinical conditions. Although the FGF21 increase may be required for CKD patients to survive, excess FGF21 causes several adverse symptoms. First, FGF21 transgenic mice are smaller than wild-type mice . The growth inhibition may be due to the ability of FGF21 to induce growth hormone resistance and lower serum levels of insulin-like growth factor-1 (IGF-1) , which may contribute to the growth retardation seen in CKD in children. Second, FGF21 trangenic mice suffer from osteopenia associated with both decreased bone formation and increased bone resorption . Although it is not clear whether serum calcium, phosphate, PTH, FGF23 and calcitriol levels are altered, FGF21 may be a prospective new entrant in the pathophysiology of CKD–mineral and bone disorder (MBD). Third, FGF21 transgenic mice display disturbed circadian behavior . This is due to FGF21 acting directly on SCN, the center of circadian rhythm regulation, because ablation of βKlotho in SCN makes FGF21 trangenic mice refractory to the disturbed circadian behavior . Thus high FGF21 may contribute to abnormal sleep/wake cycles and blood pressure fluctuations in CKD patients, which have been shown to correlate with increased cardiovascular events . Notably, solitary nucleus [nucleus tractus solitarii (NTS)] in the brainstem also coexpresses βKlotho and FGFR1c and thus is another potential target of FGF21 in the central nervous system , although the effects of FGF21 on NTS remain to be determined. Considering the fact that NTS is the center of baroreflex , it is worth testing whether FGF21 may impact on baroreflex sensitivity (BRS), because reduced BRS is an independent predictor of sudden cardiac death in CKD patients . Other CKD complications possibly attributable to high FGF21 include mood disorders, because disruption of the sleep/wake cycle due to disturbed circadian rhythms and sustained activation of the HPA axis are associated with depressive symptoms and poor prognosis in CKD patients . Future investigations to determine which complications can be attributed to increased FGF21 in CKD patients are of critical importance to justify the FGF21–βKlotho endocrine axis as a therapeutic target of CKD. THE FGF19–βKLOTHO ENDOCRINE AXIS FGF19 is a principal regulator of bile acid synthesis . In response to bile acids released into the enteric lumen upon feeding, FGF19 (FGF15 in rodents) is secreted from intestinal epithelia and enters the portal circulation. FGF19 binds to the FGFR4–βKlotho complex expressed in hepatocytes to inhibit expression of the Cyp7a1 gene, which encodes the rate-limiting enzyme for bile acid synthesis, thereby closing a negative feedback loop . FGF19 also induces metabolic responses to feeding in the liver, including an increase in protein and glycogen synthesis, independent of insulin . Expression of the FGF19 gene is transactivated directly by a nuclear receptor heterodimer composed of farnesoid X receptor (FXR) bound to bile acids and retinoid X receptor (RXR) . Ligands for FXR include both primary and secondary bile acids, such as chenodeoxycholic acid and deoxycholic acid. Because secondary bile acids are produced from primary bile acids by intestinal bacteria, enteric microbiota potentially influence FGF19 expression. Reciprocally, the composition of bile acids released into the gut influences the bacterial flora. In fact, CKD patients were reported to exhibit dysbiosis  and a blunted postprandial FGF19 response . Future studies are needed to evaluate the potential impact of the FGF19–βKlotho endocrine axis on the pathophysiology of CKD. CONCLUDING REMARKS The αKlotho gene was discovered in 1997 as the gene mutated in an obscure mouse strain exhibiting symptoms resembling those of dialysis patients, including vascular calcification, cardiac hypertrophy, sarcopenia, osteopenia, frailty and a shortened lifespan . It took almost 10 years to identify the αKlotho protein function as the coreceptor for FGF23 required for maintenance of phosphate homeostasis . At around the same time when the FGF23–αKlotho endocrine axis was discovered, hyperphosphatemia was identified as a major risk for cardiovascular morbidity and mortality [46, 74]. The synergism of these two seminal discoveries in the basic and clinical research fields have transformed our view on CKD. Followed by the discovery of the FGF21–βKlotho endocrine axis , the FGF–Klotho endocrine system has now been recognized as a central player that governs the pathophysiology of CKD. In addition, the enteric microbiome and CPPs have emerged as potential key players. Further investigations are needed to develop novel therapeutic strategies for CKD by intervening in these new players. FUNDING This article is supported in part by Japan Society for the Promotion of Science (Grant No. JP16H05302) and AMED-CREST and Japan Agency for Medical Research and Development. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Armelin HA. 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Nephrology Dialysis Transplantation – Oxford University Press
Published: May 25, 2018
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