Up Front MattersBrief Review

Forging Forward with 10 Burning Questions on FGF23 in Kidney Disease

Myles Wolf
JASN September 2010, 21 (9) 1427-1435; DOI: https://doi.org/10.1681/ASN.2009121293

Abstract

The discovery of fibroblast growth factor 23 (FGF23) as the causal factor in the pathogenesis of rare forms of hypophosphatemic rickets is rapidly reshaping our understanding of disordered mineral metabolism in chronic kidney disease (CKD). Excessive production of FGF23 by osteocytes is an appropriate compensation to help maintain normal phosphorus metabolism in these patients. Beginning in early CKD, progressive increases in levels of FGF23 enhance phosphaturia on a per-nephron basis and inhibit calcitriol production, thereby contributing centrally to the predominant phosphorus phenotype of predialysis kidney disease: normal serum phosphate, increased fractional excretion of phosphate, and calcitriol deficiency. A proliferation of studies linking phosphorus and now FGF23 excess to adverse renal and cardiovascular outcomes in patients with CKD is setting the stage for novel clinical trials that could ultimately bring FGF23 testing into the clinic. Ten burning questions must be addressed to galvanize FGF23 research further in CKD.

In only a few years, the discovery and characterization of fibroblast growth factor 23 (FGF23) is drastically changing our understanding of disordered mineral metabolism in chronic kidney disease (CKD). The journey of FGF23 from anonymity to center stage began with studies of a family of rare diseases that share a common phenotype, including hypophosphatemia, isolated urinary phosphate wasting, rickets or osteomalacia, and insufficient calcitriol production for the degree of hypophosphatemia. The main diseases in the group are X-linked hypophosphatemia (the most common), autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia, and tumor-induced osteomalacia (TIO; a sporadic form).1,2 With no known cause for the diseases, overexpression of one or more circulating phosphaturic factors, termed “phosphatonins” was hypothesized.

Genetic studies provided the breakthrough. Positional cloning revealed missense mutations in the gene encoding FGF23 on chromosome 12 in each of four families with autosomal dominant hypophosphatemic rickets, encompassing 26 affected individuals.3 These mutations were later shown to protect FGF23 from proteolytic cleavage.4,5 Confirmation of the causal role of FGF23 in the hypophosphatemic disorders came in 2001, when high expression of FGF23 was isolated from tumor cells from patients with TIO.6 The development of high-precision assays for measuring FGF23 confirmed elevated circulating levels in patients with TIO, X-linked hypophosphatemia, and ESRD compared with healthy individuals (Figure 1)7,8 and opened the door to a new era of human physiologic research on FGF23.

Figure 1.
Figure 1.

Causes of primary and secondary FGF23 excess and deficiency. Specific diseases and clinical settings and their characteristic metabolic features are listed in each quadrant corresponding to states of primary or secondary FGF23 excess or deficiency. The physiologic effects of FGF23 were originally identified in studies of rare hereditary and acquired diseases of primary FGF23 excess (left upper quadrant) and confirmed in human studies and animal models of FGF23 deficiency (right upper quadrant). Non–FGF23-dependent causes of phosphate wasting and impaired vitamin D signaling cause appropriate, secondary FGF23 deficiency (right lower quadrant), whereas CKD and deficiency of klotho, the FGF23 co-receptor, cause secondary FGF23 excess (left lower quadrant). Of all of the listed diseases and clinical settings, CKD is far and away the most common. *In contrast to absolute FGF23 deficiency, tumoral calcinosis can be caused by a defect in posttranslational glycosylation of FGF23, leading to high circulating levels of inactive C-terminal FGF23 fragments but absence of intact, biologically active FGF23. **Klotho deficiency differs metabolically from the other clinical settings in this quadrant in that 1,25 dihydroxyvitamin D (1,25D) levels are high as a result of lack of inhibition of the renal 1-α-hydroxylase by the faulty FGF23-klotho axis. Phenotypically, klotho deficiency causes a syndrome of tumoral calcinosis. ***In 1-α-hydroxylase deficiency, 1,25D levels are low, unlike the other clinical settings in this quadrant. ADHR, autosomal dominant hypophosphatemic rickets; XLH, X-linked hypophosphatemia; ARHR, autosomal recessive hypophosphatemic rickets; NaPi, sodium phosphate co-transporter; HHRH, hereditary hypophosphatemic rickets with hypercalciuria.

Normal FGF23 Physiology

FGF23 is primarily secreted by osteocytes9 and has several endocrine effects on mineral metabolism (Figure 2): FGF23 induces phosphaturia by decreasing phosphate reabsorption in the proximal tubule through downregulation of luminal sodium-phosphate co-transporters10,11; FGF23 reduces circulating levels of calcitriol by inhibiting renal 1-α hydroxylase10,11 and stimulating 24-hydroxylase,11 which catalyzes the initial step in vitamin D degradation; and FGF23 inhibits secretion of parathyroid hormone (PTH).12 These effects are dependent on the presence of klotho, which is highly expressed in the kidney and the parathyroid glands and acts as a co-receptor for FGF23 by markedly increasing the affinity of FGF23 for ubiquitous FGF receptors.13,14 These aspects of FGF23 physiology were demonstrated in studies of animals that were administered FGF23,4,10,12,15 transgenic mice that overexpress FGF23,16–19 and klotho20 and FGF23 null mice.21 Physiologic studies of normal humans were confirmatory,22–24 as were observations from patients with inactivating FGF23 or klotho mutations (Figure 1).25,26

Figure 2.
Figure 2.

Physiologic actions of FGF23. FGF23 regulates phosphorus metabolism via a series of interrelated, classic negative endocrine feedback loops (individual feedback loops are color coded). Both FGF23 and PTH stimulate phosphaturia (blue), but their effects on 1,25D are counterregulatory (PTH and 1,25D, purple; FGF23 and 1,25D, green). Whereas FGF23 clearly inhibits PTH (solid red loop) and preliminary data suggest that PTH stimulates FGF23, the latter is unproved (dashed red loop). Whether markedly elevated FGF23 levels cause collateral damage with direct injury to nonclassical target cells such as in the heart, vessels, and kidney is hypothesized but unproved (black).

Oral phosphorus loading and calcitriol stimulate and dietary phosphorus restriction inhibits FGF23 secretion.22–24,27 When a diet rich in phosphorus is consumed, high levels of FGF23 induce phosphaturia and inhibit calcitriol production, which decreases the efficiency of dietary phosphorus absorption. On a low-phosphorus diet, low FGF23 levels promote renal phosphate conservation and enhanced gut absorption of phosphorus as a result of increased calcitriol. Although this suggests serum phosphate levels are regulated within a narrow range by FGF23 despite wide fluctuation in phosphorus intake, how intake is sensed and how that signal is transduced to the FGF23-secreting osteocytes is unknown. Alternatively, FGF23 may not actually regulate serum phosphate levels. Indeed, FGF23 levels were unchanged by nondietary interventions that increased serum phosphate levels, such as intravenous phosphorus infusion28 and medical orchiectomy.29 In animal studies in which FGF23 and serum phosphate increased in parallel, it is likely that the intake of high-phosphorus chow was the primary stimulus.30 Furthermore, patients with primary hypoparathyroidism31 and those who had predialysis CKD and were given cinacalcet manifested persistent hyperphosphatemia,32 suggesting that FGF23 alone is unable to maintain normal serum phosphate levels. Thus, two critical outstanding questions in normal FGF23 physiology, which themselves are undoubtedly intertwined, are, “How is phosphate sensed, and what is FGF23 primarily regulating: the serum phosphate, local phosphate concentrations near osteocytes, phosphorus balance, bone metabolism, or calcitriol levels?”

In contrast, it is clear that the inhibitory effect of FGF23 to lower calcitriol production counterregulates the stimulatory effect of PTH, and calcitriol inhibits PTH but stimulates FGF23 secretion (Figure 2).33 Whether PTH and FGF23 share a classic negative endocrine feedback loop is likely but not yet proved. Whereas FGF23 inhibits PTH,12 it is unknown whether PTH directly stimulates FGF23 production or does so indirectly through PTH-induced increases in calcitriol. A recent study of dialysis patients in whom FGF23 levels increased significantly in response to intravenous infusion of PTH in the absence of any change in calcitriol levels suggests a direct stimulatory effect of PTH on FGF23,34 but further work is needed.

FGF23 Physiology in CKD

Although originally discovered in studies of rare hypophosphatemic disorders, the greatest clinical application of FGF23 research may ultimately lie in the management of CKD. FGF23 levels increase progressively as GFR declines beginning in early CKD,35–37 with some investigators observing significant increases already by stages 2 to 3 disease (Figure 3).35,38 By the time patients reach dialysis, levels can be up to 1000-fold higher than in healthy individuals.36 In a departure from the previous school of thought in which the gradual reduction in calcitriol levels that begins in early CKD was attributed to insufficient renal mass and thus insufficient 1-α-hydroxylase activity, it is now believed that “secondary” FGF23 excess is the primary mechanism. Likewise, “tertiary” FGF23 excess has supplanted tertiary hyperparathyroidism as the most likely mechanism of isolated posttransplantation hypophosphatemia and the associated delay in recovery of normal calcitriol production (Figure 3).39,40

Figure 3.
Figure 3.

Temporal aspects of disordered phosphorus metabolism in progressive CKD and after kidney transplantation. The x axis in the predialysis period represents GFR (left); in the postdialysis period, it represents time after kidney transplantation (right). The y axis represents circulating concentrations of the individual analytes with the temporal changes in and normal ranges of individual analytes color coded (C-terminal FGF23 [RU/ml] in red; 1,25D [pg/ml] in purple; PTH [pg/ml] in green; and phosphate [mg/dl] in blue). Current hypotheses propose increased FGF23 as the earliest alteration in mineral metabolism in CKD (1). Gradually increasing FGF23 levels cause the early decline in 1,25D levels (2) that free PTH from feedback inhibition, leading to secondary hyperparathyroidism (3). All of these changes occur long before increases in serum phosphate levels are evident (4). FGF23 and PTH levels decline rapidly in the early posttransplantation period but variably thereafter. Persistent or tertiary FGF23 excess in the posttransplantation period contributes to posttransplantation hypophosphatemia and the sluggish recovery of normal 1,25D production.

The incorporation of FGF23 into our understanding of disordered mineral metabolism helps to explain classic studies in the area. For example, when phosphorus intake and renal mass are reduced in parallel, dogs do not develop secondary hyperparathyroidism, but severe hyperparathyroidism occurred when renal mass is reduced but usual phosphorus intake continues.41 It is likely that differences in FGF23 levels account for these observations. It is also likely that a reduction in FGF23 levels as a result of decreased phosphorus intake accounted for the release of 1-α hydroxylase from feedback inhibition in studies that demonstrated a significant increase in calcitriol levels in response to dietary phosphorus restriction.42,43

Interestingly, efforts to reduce phosphorus intake as a treatment strategy to attenuate calcitriol deficiency and secondary hyperparathyroidism in CKD seem to have been mostly abandoned despite these and other promising studies suggesting benefits on bone mineralization and CKD progression.44–46 By providing an easily measurable biomarker, FGF23 offers the opportunity to revisit these strategies with an eye toward large-scale use in day-to-day clinical practice. The proliferation of several exciting studies of FGF23 excess and adverse clinical outcomes increases the urgency of developing this approach.

FGF23 and Clinical Outcomes in CKD

Several large epidemiologic studies demonstrated significant associations between increased levels of serum phosphate and adverse clinical outcomes, including more rapid progression of kidney disease, cardiovascular disease, and death.47–50 Although these studies illuminate disordered phosphorus metabolism as a therapeutic target, the serum phosphate is unlikely to be a viable biomarker in managing phosphorus metabolism in predialysis CKD because the magnitude of effect associated with changes in serum phosphate within the normal range is so small47–50; to the practicing clinician, impressive tests of significance are far less relevant than unimpressive relative risks. What is needed is a more sensitive biomarker of disordered phosphorus metabolism with greater resolution for defining risk for adverse outcomes than serum phosphate, especially when the latter is normal as it usually is in predialysis CKD.51 On the basis of initial epidemiologic studies, FGF23 is poised to fill this gap.

In a prospective study of 227 patients with nondiabetic CKD, increased FGF23 levels associated with significantly increased risk for progressive CKD.52 The effect was independent of the mostly normal serum phosphate levels, and increased FGF23 was more predictive of CKD progression than serum phosphate. Among incident hemodialysis patients, increased FGF23 levels associated independently with increased risk for mortality during the first year of therapy.53 Concomitant serum phosphate levels were only modestly associated with mortality and only among those with the most extremely elevated levels. In contrast, FGF23 demonstrated a monotonic increase in risk for mortality across the entire range of levels, and a high FGF23 level was most predictive among those with serum phosphate levels within the acceptable range. The dosage-response relationship between increasing FGF23 and mortality was confirmed in a study that extended these results to prevalent dialysis patients.54 In aggregate, these data suggest that FGF23 excess is a more robust predictor of adverse outcomes in CKD than serum phosphate levels.

Because cardiovascular disease is the leading cause of death in patients with CKD,55 it is likely the association between FGF23 excess and mortality is mediated by increased cardiovascular risk. Several studies support this view. In a population of predialysis patients with CKD and healthy patients with normal serum phosphate levels, increased FGF23 associated independently with increased left ventricular mass index and significantly greater prevalence of left ventricular hypertrophy.56 These results were confirmed and extended to a large population of elderly patients who had preserved renal function and in whom increased FGF23 levels were also independently associated with endothelial dysfunction and vascular stiffness.57,58 On the basis of presentations at the American Society of Nephrology's Renal Week 2009,59–61 we can expect numerous additional reports confirming the association between FGF23 excess and adverse outcomes.

Potential Clinical Implications of FGF23 in CKD

Current data suggest that FGF23 could herald a new paradigm in the treatment of patients with CKD. Just as PTH screening is used to determine which patients with CKD and normal serum calcium levels should be considered for vitamin D therapy, so, too, could FGF23 screening help to identify which patients with CKD and normal serum phosphate levels benefit from dietary phosphorus restriction and phosphorus binders. This would represent a significant departure from current standards of care, which emphasize initiating treatment when overt hyperphosphatemia develops, which is often long after FGF23 levels have already increased substantially (Figure 3).35 Thus, FGF23 screening could identify far more candidates for phosphorus-related therapies far earlier in their course of CKD, when the benefits of early intervention are maximal. Conservatively assuming that 50% of patients with stages 2 through 4 CKD in the United States manifest an elevated FGF23 level,62 FGF23 screening could expand the target population for phosphorus-related therapies from approximately 0.4 million dialysis patients and predialysis patients with hyperphosphatemia to >7 million individuals, nearly a 2000% increase.

Before FGF23 can be integrated into CKD practice, it must traverse additional milestones. We must demonstrate that increased FGF23 is a risk factor for adverse outcomes in predialysis CKD and that elevated FGF23 levels can be safely lowered in this population. Then, we must prove in a randomized trial that lowering elevated FGF23 levels reduces the risk for adverse outcomes compared with placebo. These critical issues were presented in detail in recent reviews that focused on the clinical aspects of FGF23 in the future.62 The next section highlights 10 burning questions on FGF23 in CKD, the answers to which will likely shape the FGF23 research portfolio in upcoming years.

Ten Burning Questions on FGF23 in CKD

1. What Is the Normal Range of FGF23, and What Is the Prevalence of an Abnormally High Level at Various Stages of CKD?

These are among the most basic and important outstanding questions in human FGF23 research. The ability to recognize which patients with CKD have high FGF23 levels requires knowledge of what is normal, yet there have been no population-based studies to define normal FGF23 ranges across various ages, genders, and races and in health, CKD, or other disease states.

2. Besides Dietary Phosphorus and Calcitriol, What Are the Determinants of FGF23 Levels in CKD?

Although serum phosphate and FGF23 levels correlate strongly,36,54 there are no data to support a direct effect of serum phosphate on FGF23 secretion in health or CKD. Although it is possible that prolonged severe hyperphosphatemia in dialysis patients might theoretically stimulate FGF23 secretion directly, existing data suggest that FGF23 may not be primarily regulating (and thus stimulated by perturbations in) serum phosphate levels, but perhaps, instead, it regulates phosphorus balance, vitamin D physiology, or bone metabolism, as recent studies suggested.38,63,64

Whether kidney disease itself contributes to raising FGF23 levels directly is also unclear. For example, the ailing kidney could express a factor that stimulates FGF23, decrease expression of an inhibitor, or contribute to diminished uptake or decreased urinary clearance of the hormone. Current evidence suggests there is indeed increased production of FGF23 as early as stage 2 CKD,38 and the concept of increased production is supported by persistently elevated FGF23 levels 12 months after kidney transplantation despite a well-functioning allograft.39 The clearance of FGF23 in CKD by cellular uptake, urinary excretion, or dialysis must be studied, and we must also determine the impact of residual renal function and dialysis vintage before FGF23 levels in dialysis patients can be accurately interpreted. Finally, intravenous iron stimulates FGF23 secretion.65 Although the mechanism and relevance require further study, this could have important implications for dialysis patients who are frequently administered iron.

3. Elevated FGF23 and PTH Levels in CKD: Which Comes First?

Although FGF23 and PTH are often both elevated in CKD, it remains unknown which rises first and whether the pattern is uniform across all patients. Although the distinction may be purely academic for most patients with CKD in whom both are high, defining the sequence of early pathophysiologic events could shed light on the optimal initial therapeutic management of disordered mineral metabolism: whether to start with vitamin D, phosphorus therapies, or a combination of both. To date, limited data suggest that FGF23 excess precedes significant elevations in PTH levels,66 but there are dissenting views.67

4. What Is the Ideal Assay to Measure Circulating FGF23 Levels in CKD?

There are currently two types of assays for measuring FGF23. C-terminal assays, which recognize two epitopes in the C-terminus, capture both intact FGF23 and its C-terminal fragment.7 Intact assays capture only intact FGF23 because the two epitopes flank the cleavage site.68 Although several studies demonstrated high correlation between the two assays even in CKD,23,52,53,68 it is often assumed that the markedly elevated FGF23 levels in patients with CKD may represent accumulation of inactive C-terminal fragments. This view likely stems from the experience with PTH assays; however, unlike PTH, there are limited data in support of accumulation of FGF23 fragments in CKD.8 Indeed, a recent study found virtually all circulating FGF23 is intact and biologically active in peritoneal dialysis patients.68 This suggests that FGF23 is secreted intact exclusively and undergoes little if any degradation in circulation, both features in sharp contrast to PTH. Although additional confirmatory studies are needed, it seems clear that reliable results in CKD can be gleaned from either assay strategy.

5. How Do FGF23 Levels Differ in Specific CKD Subpopulations?

Most clinical studies of FGF23 have been relatively small, and the few larger studies were racially and ethnically homogeneous. In the mortality study of 400 incident hemodialysis patients, black and Hispanic patients demonstrated approximately 20 to 30% lower FGF23 levels compared with white patients.53 Although large population-based validation studies are needed, these differences are plausible when considering the known racial and ethnic differences in mineral metabolism, whereby nonwhite groups have higher serum phosphate and calcitriol levels despite higher rates of nutritional vitamin D deficiency and elevated PTH levels compared with white groups.69–71

Whether FGF23 levels differ according to the cause of kidney disease is unknown. Most studies have found no association between FGF23 and age, but pediatric studies involving very young participants are needed given the differences in phosphorus physiology in infants and toddlers, who manifest markedly higher serum phosphate levels and growth rates than adults. Finally, estradiol stimulates FGF23,72 and one study reported higher levels in healthy women,7 but this, too, requires systematic study.

6. Is FGF23 Excess or Klotho Deficiency the True Risk Factor?

Deficiency of klotho, the co-receptor for FGF23, associates with hyperphosphatemia and markedly elevated levels of FGF23.20,26 Just as FGF23 levels rise with progressive loss of kidney function, it is thought that renal expression of klotho declines.73 This suggests that CKD may be a state of progressive renal resistance to FGF23.74 Given the association between klotho deficiency and vascular calcification, accelerated aging, and premature death,75 it is proposed that the association between FGF23 excess and adverse outcomes in CKD is mediated by klotho deficiency.74 The main limitations to addressing this important hypothesis are the lack of a reliable in vivo assay for circulating klotho and uncertainty over the relative importance of the transmembrane versus the soluble form.

7. Does FGF23 Exert Direct Toxicity on Tissues, or Is It Simply a Biomarker?

Underlying its association with adverse outcomes, FGF23 excess could be a biomarker of phosphorus excess or calcitriol deficiency, or it could be directly toxic to nontraditional target organs such as the cardiovascular system. Given the lack of klotho expression in the cardiovascular system, any direct effect of FGF23 would presumably be independent of klotho. There are reports of low-affinity, klotho-independent binding of FGF23 to FGF receptors,76,77 suggesting the markedly elevated FGF23 concentrations observed in CKD could theoretically mimic the effects of basic FGF (FGF2), which has been implicated in myocardial hypertrophy.78,79 Additional research is required to examine this question, which has substantial clinical implications.

8. Can FGF23 Levels be Lowered in CKD with Standard or Emerging Therapies?

If a markedly elevated FGF23 level is directly toxic, then reducing the level or blocking its effect would emerge as a novel therapeutic target in CKD. Short-term studies of dialysis patients demonstrated a modest reduction in FGF23 levels in response to cinacalcet and a modest increase in levels after treatment with active vitamin D.80,81 Whether these effects prove to be clinically relevant when considered against the background of massive elevations in levels of FGF23 in dialysis patients is unclear. Administering a more targeted mAb that neutralizes FGF23 is theoretically attractive (but not yet available) for dialysis patients who do not depend on native renal clearance of phosphorus. In predialysis CKD, alternative strategies would be needed because effective FGF23 blockade could replicate the physiology of FGF23 null mice21 or patients with tumoral calcinosis25: severe hyperphosphatemia and hypercalcemia as a result of increased calcitriol levels with extensive calcification. In that setting, it would be essential to reduce the root cause of FGF23 elevation, likely by using dietary phosphorus restriction and phosphorus binders. Unlike neutralizing antibodies, these interventions would also be expected to be beneficial if FGF23 is a biomarker of adverse outcomes associated with phosphorus excess rather than a direct toxin. Animal and pilot studies of patients with CKD demonstrated the potential efficacy of binders,82–84 but larger, more prolonged studies that also emphasize the impact of dietary restriction are needed.

9. Does Excessive FGF23 Inhibit Peripheral 1-α-Hydroxylase?

The optimum approach to treating deficiencies in the vitamin D axis in CKD is controversial. Although active vitamin D therapy associated with a significant survival benefit in observational studies,85 there is growing interest in treating patients with inactive vitamin D precursors to decrease or obviate altogether the requirement for exogenous active vitamin D.86 The basis for this approach is that peripheral activation of vitamin D precursors by extrarenal cells that express CYP27B1 (1-α-hydroxylase) will generate adequate amounts of calcitriol locally87; however, few studies have examined the regulation of peripheral CYP27B1 and whether it functions normally in CKD in the setting of very high FGF23 levels. In a recent report,88 cholecalciferol repletion in dialysis patients induced calcitriol-dependent protein expression in monocytes, suggesting intact peripheral CYP27B1, but the effect could have been mediated by the increase in systemic (from the kidney) calcitriol levels that were observed. Determining whether a markedly increased FGF23 level inhibits peripheral CYP27B1 will strengthen the physiologic basis for designing optimal vitamin D regimens in CKD.

10. What Is the Role of FGF23 in Acute Renal Failure?

There are no systematic studies of FGF23 levels or its possible effects in acute renal failure. There is only a single report of increased FGF23 levels in a case of acute renal failure that was caused by rhabdomyolysis.89 Observational studies should measure FGF23 levels at multiple time points in the course of acute renal failure, in several of its varied etiologies, and should determine whether there is any relationship between levels and subsequent outcomes.

Conclusions

In less than a decade since its discovery, FGF23 has been elevated to the forefront of CKD research and has the potential to transform the clinical management of disordered mineral metabolism in CKD. Such rapid progress represents an extraordinary case study in the power of modern multidisciplinary translational research in which human genomics, sophisticated cell biology, human physiologic research, epidemiology, and clinical trials unite with old-fashioned clinical observation. Expectedly, there is still much to learn about fundamental aspects of FGF23 physiology in general and in CKD in particular, and many more human studies are needed before FGF23 testing can be integrated into clinical practice. What is clear is that disordered phosphorus metabolism in CKD will continue to be an active and exciting area for years to come.

Disclosures

M.W. has received research support from Shire and honoraria from Abbott, Amgen, Davita, Genzyme, Mitsubishi, and Shire.

Acknowledgments

This work was supported by grants DK076116 and DK081374 from the National Institutes of Health.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

REFERENCES

  1. 1.↵
    1. Quarles LD
    : FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab 285: E1–E9, 2003
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Strom TM,
    2. Juppner H
    : PHEX, FGF23, DMP1 and beyond. Curr Opin Nephrol Hypertens 17: 357–362, 2008
    OpenUrlCrossRefPubMed
  3. 3.↵
    Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 26: 345–348, 2000
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Shimada T,
    2. Muto T,
    3. Urakawa I,
    4. Yoneya T,
    5. Yamazaki Y,
    6. Okawa K,
    7. Takeuchi Y,
    8. Fujita T,
    9. Fukumoto S,
    10. Yamashita T
    : Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143: 3179–3182, 2002
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Bai XY,
    2. Miao D,
    3. Goltzman D,
    4. Karaplis AC
    : The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency. J Biol Chem 278: 9843–9849, 2003
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Shimada T,
    2. Mizutani S,
    3. Muto T,
    4. Yoneya T,
    5. Hino R,
    6. Takeda S,
    7. Takeuchi Y,
    8. Fujita T,
    9. Fukumoto S,
    10. Yamashita T
    : Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 98: 6500–6505, 2001
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Jonsson KB,
    2. Zahradnik R,
    3. Larsson T,
    4. White KE,
    5. Sugimoto T,
    6. Imanishi Y,
    7. Yamamoto T,
    8. Hampson G,
    9. Koshiyama H,
    10. Ljunggren O,
    11. Oba K,
    12. Yang IM,
    13. Miyauchi A,
    14. Econs MJ,
    15. Lavigne J,
    16. Juppner H
    : Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 348: 1656–1663, 2003
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Weber TJ,
    2. Liu S,
    3. Indridason OS,
    4. Quarles LD
    : Serum FGF23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res 18: 1227–1234, 2003
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Quarles LD
    : Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 118: 3820–3828, 2008
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Saito H,
    2. Kusano K,
    3. Kinosaki M,
    4. Ito H,
    5. Hirata M,
    6. Segawa H,
    7. Miyamoto K,
    8. Fukushima N
    : Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production. J Biol Chem 278: 2206–2211, 2003
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Shimada T,
    2. Hasegawa H,
    3. Yamazaki Y,
    4. Muto T,
    5. Hino R,
    6. Takeuchi Y,
    7. Fujita T,
    8. Nakahara K,
    9. Fukumoto S,
    10. Yamashita T
    : FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19: 429–435, 2004
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Ben-Dov IZ,
    2. Galitzer H,
    3. Lavi-Moshayoff V,
    4. Goetz R,
    5. Kuro-o M,
    6. Mohammadi M,
    7. Sirkis R,
    8. Naveh-Many T,
    9. Silver J
    : The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117: 4003–4008, 2007
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Urakawa I,
    2. Yamazaki Y,
    3. Shimada T,
    4. Iijima K,
    5. Hasegawa H,
    6. Okawa K,
    7. Fujita T,
    8. Fukumoto S,
    9. Yamashita T
    : Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770–774, 2006
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Kurosu H,
    2. Ogawa Y,
    3. Miyoshi M,
    4. Yamamoto M,
    5. Nandi A,
    6. Rosenblatt KP,
    7. Baum MG,
    8. Schiavi S,
    9. Hu MC,
    10. Moe OW,
    11. Kuro-o M
    : Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281: 6120–6123, 2006
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Perwad F,
    2. Zhang MY,
    3. Tenenhouse HS,
    4. Portale AA
    : Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. Am J Physiol Renal Physiol 293: F1577–F1583, 2007
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Shimada T,
    2. Yoneya T,
    3. Hino R,
    4. Takeuchi Y,
    5. Fukumoto S,
    6. Yamashita T
    : Transgenic mice expressing FGF23 demonstrate hypophosphatemia with low serum 1,25-dihydroxyvitamin D and rickets/osteomalacia. J Bone Miner Res 16: S151, 2001
    OpenUrl
  17. 17.↵
    1. Bai X,
    2. Miao D,
    3. Li J,
    4. Goltzman D,
    5. Karaplis AC
    : Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. Endocrinology 145: 5269–5279, 2004
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Shimada T,
    2. Urakawa I,
    3. Yamazaki Y,
    4. Hasegawa H,
    5. Hino R,
    6. Yoneya T,
    7. Takeuchi Y,
    8. Fujita T,
    9. Fukumoto S,
    10. Yamashita T
    : FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 314: 409–414, 2004
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Larsson T,
    2. Marsell R,
    3. Schipani E,
    4. Ohlsson C,
    5. Ljunggren O,
    6. Tenenhouse HS,
    7. Juppner H,
    8. Jonsson KB
    : Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology 145: 3087–3094, 2004
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Tsujikawa H,
    2. Kurotaki Y,
    3. Fujimori T,
    4. Fukuda K,
    5. Nabeshima Y
    : Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 17: 2393–2403, 2003
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Sitara D,
    2. Razzaque MS,
    3. Hesse M,
    4. Yoganathan S,
    5. Taguchi T,
    6. Erben RG,
    7. Juppner H,
    8. Lanske B
    : Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23: 421–432, 2004
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Antoniucci DM,
    2. Yamashita T,
    3. Portale AA
    : Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab 91: 3144–3149, 2006
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Burnett SM,
    2. Gunawardene SC,
    3. Bringhurst FR,
    4. Juppner H,
    5. Lee H,
    6. Finkelstein JS
    : Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res 21: 1187–1196, 2006
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Ferrari SL,
    2. Bonjour JP,
    3. Rizzoli R
    : FGF-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab 90: 1519–1524, 2005
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Benet-Pages A,
    2. Orlik P,
    3. Strom TM,
    4. Lorenz-Depiereux B
    : An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 14: 385–390, 2005
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Ichikawa S,
    2. Imel EA,
    3. Kreiter ML,
    4. Yu X,
    5. Mackenzie DS,
    6. Sorenson AH,
    7. Goetz R,
    8. Mohammadi M,
    9. White KE,
    10. Econs MJ
    : A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117: 2684–2691, 2007
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Saito H,
    2. Maeda A,
    3. Ohtomo S,
    4. Hirata M,
    5. Kusano K,
    6. Kato S,
    7. Ogata E,
    8. Segawa H,
    9. Miyamoto K,
    10. Fukushima N
    : Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 280: 2543–2549, 2005
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Ito N,
    2. Fukumoto S,
    3. Takeuchi Y,
    4. Takeda S,
    5. Suzuki H,
    6. Yamashita T,
    7. Fujita T
    : Effect of acute changes of serum phosphate on fibroblast growth factor (FGF)23 levels in humans. J Bone Miner Metab 25: 419–422, 2007
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Burnett-Bowie SM,
    2. Mendoza N,
    3. Leder BZ
    : Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men. Bone 40: 913–918, 2007
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Perwad F,
    2. Azam N,
    3. Zhang MY,
    4. Yamashita T,
    5. Tenenhouse HS,
    6. Portale AA
    : Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146: 5358–5364, 2005
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Gupta A,
    2. Winer K,
    3. Econs MJ,
    4. Marx SJ,
    5. Collins MT
    : FGF-23 is elevated by chronic hyperphosphatemia. J Clin Endocrinol Metab 89: 4489–4492, 2004
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Charytan C,
    2. Coburn JW,
    3. Chonchol M,
    4. Herman J,
    5. Lien YH,
    6. Liu W,
    7. Klassen PS,
    8. McCary LC,
    9. Pichette V
    : Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis. Am J Kidney Dis 46: 58–67, 2005
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Liu S,
    2. Tang W,
    3. Zhou J,
    4. Stubbs JR,
    5. Luo Q,
    6. Pi M,
    7. Quarles LD
    : Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17: 1305–1315, 2006
    OpenUrlAbstract/FREE Full Text
  34. 34.↵
    1. Wesseling-Perry K,
    2. Gales B,
    3. Wang H,
    4. Elashoff RM,
    5. Juppner H,
    6. Salusky IB
    : Skeletal responses to PTH infusion: A comparison between low and high turnover renal osteodystrophy [Abstract]. J Am Soc Nephrol 20: 54A, 2009
    OpenUrl
  35. 35.↵
    1. Gutierrez O,
    2. Isakova T,
    3. Rhee E,
    4. Shah A,
    5. Holmes J,
    6. Collerone G,
    7. Juppner H,
    8. Wolf M
    : Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16: 2205–2215, 2005
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Larsson T,
    2. Nisbeth U,
    3. Ljunggren O,
    4. Juppner H,
    5. Jonsson KB
    : Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 64: 2272–2279, 2003
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Shigematsu T,
    2. Kazama JJ,
    3. Yamashita T,
    4. Fukumoto S,
    5. Hosoya T,
    6. Gejyo F,
    7. Fukagawa M
    : Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis 44: 250–256, 2004
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Pereira RC,
    2. Juppner H,
    3. Azucena-Serrano CE,
    4. Yadin O,
    5. Salusky IB,
    6. Wesseling-Perry K
    : Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. Bone 45: 1161–1168, 2009
    OpenUrlCrossRefPubMed
  39. 39.↵
    1. Bhan I,
    2. Shah A,
    3. Holmes J,
    4. Isakova T,
    5. Gutierrez O,
    6. Burnett SM,
    7. Juppner H,
    8. Wolf M
    : Post-transplant hypophosphatemia: Tertiary ‘hyper-phosphatoninism'? Kidney Int 70: 1486–1494, 2006
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Evenepoel P,
    2. Naesens M,
    3. Claes K,
    4. Kuypers D,
    5. Vanrenterghem Y
    : Tertiary ‘hyperphosphatoninism' accentuates hypophosphatemia and suppresses calcitriol levels in renal transplant recipients. Am J Transplant 7: 1193–1200, 2007
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Slatopolsky E,
    2. Caglar S,
    3. Pennell JP,
    4. Taggart DD,
    5. Canterbury JM,
    6. Reiss E,
    7. Bricker NS
    : On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest 50: 492–499, 1971
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Portale AA,
    2. Booth BE,
    3. Halloran BP,
    4. Morris RC Jr.
    : Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 73: 1580–1589, 1984
    OpenUrlCrossRefPubMed
  43. 43.↵
    1. Martinez I,
    2. Saracho R,
    3. Montenegro J,
    4. Llach F
    : The importance of dietary calcium and phosphorous in the secondary hyperparathyroidism of patients with early renal failure. Am J Kidney Dis 29: 496–502, 1997
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Maschio G,
    2. Tessitore N,
    3. D'Angelo A,
    4. Bonucci E,
    5. Lupo A,
    6. Valvo E,
    7. Loschiavo C,
    8. Fabris A,
    9. Morachiello P,
    10. Previato G,
    11. Fiaschi E
    : Early dietary phosphorus restriction and calcium supplementation in the prevention of renal osteodystrophy. Am J Clin Nutr 33: 1546–1554, 1980
    OpenUrlFREE Full Text
  45. 45.↵
    1. Alfrey AC
    : Effect of dietary phosphate restriction on renal function and deterioration. Am J Clin Nutr 47: 153–156, 1988
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    1. Ibels LS,
    2. Alfrey AC,
    3. Haut L,
    4. Huffer WE
    : Preservation of function in experimental renal disease by dietary restriction of phosphate. N Engl J Med 298: 122–126, 1978
    OpenUrlCrossRefPubMed
  47. 47.↵
    1. Kestenbaum B,
    2. Sampson JN,
    3. Rudser KD,
    4. Patterson DJ,
    5. Seliger SL,
    6. Young B,
    7. Sherrard DJ,
    8. Andress DL
    : Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 16: 520–528, 2005
    OpenUrlAbstract/FREE Full Text
  48. 48.↵
    1. Dhingra R,
    2. Sullivan LM,
    3. Fox CS,
    4. Wang TJ,
    5. D'Agostino RB Sr.,
    6. Gaziano JM,
    7. Vasan RS
    : Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 167: 879–885, 2007
    OpenUrlCrossRefPubMed
  49. 49.↵
    1. Norris KC,
    2. Greene T,
    3. Kopple J,
    4. Lea J,
    5. Lewis J,
    6. Lipkowitz M,
    7. Miller P,
    8. Richardson A,
    9. Rostand S,
    10. Wang X,
    11. Appel LJ
    : Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease. J Am Soc Nephrol 17: 2928–2936, 2006
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    1. Tonelli M,
    2. Sacks F,
    3. Pfeffer M,
    4. Gao Z,
    5. Curhan G
    : Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112: 2627–2633, 2005
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    1. Levin A,
    2. Bakris GL,
    3. Molitch M,
    4. Smulders M,
    5. Tian J,
    6. Williams LA,
    7. Andress DL
    : Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: Results of the Study to Evaluate Early Kidney Disease. Kidney Int 71: 31–38, 2007
    OpenUrlCrossRefPubMed
  52. 52.↵
    1. Fliser D,
    2. Kollerits B,
    3. Neyer U,
    4. Ankerst DP,
    5. Lhotta K,
    6. Lingenhel A,
    7. Ritz E,
    8. Kronenberg F,
    9. Kuen E,
    10. Konig P,
    11. Kraatz G,
    12. Mann JF,
    13. Muller GA,
    14. Kohler H,
    15. Riegler P
    : Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: The Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 18: 2600–2608, 2007
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    1. Gutierrez OM,
    2. Mannstadt M,
    3. Isakova T,
    4. Rauh-Hain JA,
    5. Tamez H,
    6. Shah A,
    7. Smith K,
    8. Lee H,
    9. Thadhani R,
    10. Juppner H,
    11. Wolf M
    : Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359: 584–592, 2008
    OpenUrlCrossRefPubMed
  54. 54.↵
    1. Jean G,
    2. Terrat JC,
    3. Vanel T,
    4. Hurot JM,
    5. Lorriaux C,
    6. Mayor B,
    7. Chazot C
    : High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant 24: 2792–2796, 2009
    OpenUrlCrossRefPubMed
  55. 55.↵
    1. Levin A
    : Clinical epidemiology of cardiovascular disease in chronic kidney disease prior to dialysis. Semin Dial 16: 101–105, 2003
    OpenUrlCrossRefPubMed
  56. 56.↵
    1. Gutierrez OM,
    2. Januzzi JL,
    3. Isakova T,
    4. Laliberte K,
    5. Smith K,
    6. Collerone G,
    7. Sarwar A,
    8. Hoffmann U,
    9. Coglianese E,
    10. Christenson R,
    11. Wang TJ,
    12. deFilippi C,
    13. Wolf M
    : Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119: 2545–2552, 2009
    OpenUrlAbstract/FREE Full Text
  57. 57.↵
    1. Mirza MA,
    2. Larsson A,
    3. Lind L,
    4. Larsson TE
    : Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis 205: 385–390, 2009
    OpenUrlCrossRefPubMed
  58. 58.↵
    1. Mirza MA,
    2. Hansen T,
    3. Johansson L,
    4. Ahlstrom H,
    5. Larsson A,
    6. Lind L,
    7. Larsson TE
    : Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrol Dial Transplant 24: 3125–3131, 2009
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Kendrick JB,
    2. Cheung AK,
    3. Kaufman JS,
    4. Greene T,
    5. Roberts W,
    6. Smits G,
    7. Chonchol M
    : Fibroblast growth factor-23 and the risk of death and cardiovascular events among patients with chronic kidney disease [Abstract]. J Am Soc Nephrol 20: 540A, 2009
    OpenUrl
  60. 60.↵
    1. Kendrick JB,
    2. Cheung AK,
    3. Kaufman JS,
    4. Greene T,
    5. Roberts W,
    6. Smits G,
    7. Chonchol M
    : Fibroblast growth factor-23 and progression to dialysis in patients with advanced kidney disease [Abstract]. J Am Soc Nephrol 20: 542A, 2009
    OpenUrl
  61. 61.↵
    1. Titan SM,
    2. Zatz R,
    3. Jorgetti V,
    4. Graciolli FG,
    5. dos Reis LM,
    6. Moysés RM
    : FGF-23 as a predictor of renal outcome in diabetic nephropathy [Abstract]. J Am Soc Nephrol 20: 540A, 2009
    OpenUrl
  62. 62.↵
    1. Isakova T,
    2. Gutierrez OM,
    3. Wolf M
    : A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease. Kidney Int 76: 705–716, 2009
    OpenUrlCrossRefPubMed
  63. 63.↵
    1. Wesseling-Perry K,
    2. Pereira RC,
    3. Wang H,
    4. Elashoff RM,
    5. Sahney S,
    6. Gales B,
    7. Juppner H,
    8. Salusky IB
    : Relationship between plasma fibroblast growth factor-23 concentration and bone mineralization in children with renal failure on peritoneal dialysis. J Clin Endocrinol Metab 94: 511–517, 2009
    OpenUrlCrossRefPubMed
  64. 64.↵
    1. Samadfam R,
    2. Richard C,
    3. Nguyen-Yamamoto L,
    4. Bolivar I,
    5. Goltzman D
    : Bone formation regulates circulating concentrations of fibroblast growth factor 23. Endocrinology 150: 4835–4845, 2009
    OpenUrlCrossRefPubMed
  65. 65.↵
    1. Schouten BJ,
    2. Hunt PJ,
    3. Livesey JH,
    4. Frampton CM,
    5. Soule SG
    : FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: A prospective study. J Clin Endocrinol Metab 94: 2332–2337, 2009
    OpenUrlCrossRefPubMed
  66. 66.↵
    1. Isakova T,
    2. Gutierrez O,
    3. Shah A,
    4. Castaldo L,
    5. Holmes J,
    6. Lee H,
    7. Wolf M
    : Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol 19: 615–623, 2008
    OpenUrlAbstract/FREE Full Text
  67. 67.↵
    1. Westerberg PA,
    2. Linde T,
    3. Wikstrom B,
    4. Ljunggren O,
    5. Stridsberg M,
    6. Larsson TE
    : Regulation of fibroblast growth factor-23 in chronic kidney disease. Nephrol Dial Transplant 22: 3202–3207, 2007
    OpenUrlCrossRefPubMed
  68. 68.↵
    1. Shimada T,
    2. Urakawa I,
    3. Isakova T,
    4. Yamazaki Y,
    5. Epstein M,
    6. Wesseling-Perry K,
    7. Wolf M,
    8. Salusky IB,
    9. Juppner H
    : Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active. J Clin Endocrinol Metab 95: 578–585, 2010
    OpenUrlCrossRefPubMed
  69. 69.↵
    1. Bell NH,
    2. Epstein S,
    3. Greene A,
    4. Shary J,
    5. Oexmann MJ,
    6. Shaw S
    : Evidence for alteration of the vitamin D-endocrine system in obese subjects. J Clin Invest 76: 370–373, 1985
    OpenUrlCrossRefPubMed
  70. 70.↵
    1. Foley RN,
    2. Wang C,
    3. Ishani A,
    4. Collins AJ
    : NHANES III: Influence of race on GFR thresholds and detection of metabolic abnormalities. J Am Soc Nephrol 18: 2575–2582, 2007
    OpenUrlAbstract/FREE Full Text
  71. 71.↵
    1. Gutierrez OM,
    2. Isakova T,
    3. Andress DL,
    4. Levin A,
    5. Wolf M
    : Prevalence and severity of disordered mineral metabolism in blacks with chronic kidney disease. Kidney Int 73: 956–962, 2008
    OpenUrlCrossRefPubMed
  72. 72.↵
    1. Carrillo-Lopez N,
    2. Roman-Garcia P,
    3. Rodriguez-Rebollar A,
    4. Fernandez-Martin JL,
    5. Naves-Diaz M,
    6. Cannata-Andia JB
    : Indirect regulation of PTH by estrogens may require FGF23. J Am Soc Nephrol 20: 2009–2017, 2009
    OpenUrlAbstract/FREE Full Text
  73. 73.↵
    1. Koh N,
    2. Fujimori T,
    3. Nishiguchi S,
    4. Tamori A,
    5. Shiomi S,
    6. Nakatani T,
    7. Sugimura K,
    8. Kishimoto T,
    9. Kinoshita S,
    10. Kuroki T,
    11. Nabeshima Y
    : Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 280: 1015–1020, 2001
    OpenUrlCrossRefPubMed
  74. 74.↵
    1. Kuro-o M
    . Klotho in chronic kidney disease: What's new? Nephrol Dial Transplant 24: 1705–1708, 2009
    OpenUrlCrossRefPubMed
  75. 75.↵
    1. Kuro-o M,
    2. Matsumura Y,
    3. Aizawa H,
    4. Kawaguchi H,
    5. Suga T,
    6. Utsugi T,
    7. Ohyama Y,
    8. Kurabayashi M,
    9. Kaname T,
    10. Kume E,
    11. Iwasaki H,
    12. Iida A,
    13. Shiraki-Iida T,
    14. Nishikawa S,
    15. Nagai R,
    16. Nabeshima YI
    : Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390: 45–51, 1997
    OpenUrlCrossRefPubMed
  76. 76.↵
    1. Yu X,
    2. Ibrahimi OA,
    3. Goetz R,
    4. Zhang F,
    5. Davis SI,
    6. Garringer HJ,
    7. Linhardt RJ,
    8. Ornitz DM,
    9. Mohammadi M,
    10. White KE
    : Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology 146: 4647–4656, 2005
    OpenUrlCrossRefPubMed
  77. 77.↵
    1. Wang H,
    2. Yoshiko Y,
    3. Yamamoto R,
    4. Minamizaki T,
    5. Kozai K,
    6. Tanne K,
    7. Aubin JE,
    8. Maeda N
    : Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro. J Bone Miner Res 23: 939–948, 2008
    OpenUrlCrossRefPubMed
  78. 78.↵
    1. Corda S,
    2. Mebazaa A,
    3. Gandolfini MP,
    4. Fitting C,
    5. Marotte F,
    6. Peynet J,
    7. Charlemagne D,
    8. Cavaillon JM,
    9. Payen D,
    10. Rappaport L,
    11. Samuel JL
    : Trophic effect of human pericardial fluid on adult cardiac myocytes: Differential role of fibroblast growth factor-2 and factors related to ventricular hypertrophy. Circ Res 81: 679–687, 1997
    OpenUrlAbstract/FREE Full Text
  79. 79.↵
    1. Scheinowitz M,
    2. Kotlyar A,
    3. Zimand S,
    4. Ohad D,
    5. Leibovitz I,
    6. Bloom N,
    7. Goldberg I,
    8. Nass D,
    9. Engelberg S,
    10. Savion N,
    11. Eldar M
    : Basic fibroblast growth factor induces myocardial hypertrophy following acute infarction in rats. Exp Physiol 83: 585–593, 1998
    OpenUrlCrossRefPubMed
  80. 80.↵
    1. Wetmore JB,
    2. Liu S,
    3. Krebill R,
    4. Menard R,
    5. Quarles LD
    : Effects of cinacalcet and concurrent low-dose vitamin D on FGF23 levels in ESRD. Clin J Am Soc Nephrol 5: 110–116, 2010
    OpenUrlAbstract/FREE Full Text
  81. 81.↵
    1. Nishi H,
    2. Nii-Kono T,
    3. Nakanishi S,
    4. Yamazaki Y,
    5. Yamashita T,
    6. Fukumoto S,
    7. Ikeda K,
    8. Fujimori A,
    9. Fukagawa M
    : Intravenous calcitriol therapy increases serum concentrations of fibroblast growth factor-23 in dialysis patients with secondary hyperparathyroidism. Nephron Clin Pract 101: c94–c99, 2005
    OpenUrlCrossRefPubMed
  82. 82.↵
    1. Koiwa F,
    2. Kazama JJ,
    3. Tokumoto A,
    4. Onoda N,
    5. Kato H,
    6. Okada T,
    7. Nii-Kono T,
    8. Fukagawa M,
    9. Shigematsu T
    : Sevelamer hydrochloride and calcium bicarbonate reduce serum fibroblast growth factor 23 levels in dialysis patients. Ther Apher Dial 9: 336–339, 2005
    OpenUrlCrossRefPubMed
  83. 83.↵
    1. Oliveira RB,
    2. Cancela AL,
    3. Graciolli FG,
    4. Dos Reis LM,
    5. Draibe SA,
    6. Cuppari L,
    7. Carvalho AB,
    8. Jorgetti V,
    9. Canziani ME,
    10. Moyses RM
    : Early control of PTH and FGF23 in normophosphatemic CKD patients: A new target in CKD-MBD therapy? Clin J Am Soc Nephrol 5: 286–291, 2010
    OpenUrlAbstract/FREE Full Text
  84. 84.↵
    1. Nagano N,
    2. Miyata S,
    3. Abe M,
    4. Kobayashi N,
    5. Wakita S,
    6. Yamashita T,
    7. Wada M
    : Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats. Kidney Int 69: 531–537, 2006
    OpenUrlCrossRefPubMed
  85. 85.↵
    1. Teng M,
    2. Wolf M,
    3. Ofsthun MN,
    4. Lazarus JM,
    5. Hernan MA,
    6. Camargo CA Jr.,
    7. Thadhani R
    : Activated injectable vitamin D and hemodialysis survival: A historical cohort study. J Am Soc Nephrol 16: 1115–1125, 2005
    OpenUrlAbstract/FREE Full Text
  86. 86.↵
    1. Jean G,
    2. Charra B,
    3. Chazot C
    : Vitamin D deficiency and associated factors in hemodialysis patients. J Ren Nutr 18: 395–399, 2008
    OpenUrlCrossRefPubMed
  87. 87.↵
    1. Lambert PW,
    2. Stern PH,
    3. Avioli RC,
    4. Brackett NC,
    5. Turner RT,
    6. Greene A,
    7. Fu IY,
    8. Bell NH
    : Evidence for extrarenal production of 1 alpha,25-dihydroxyvitamin D in man. J Clin Invest 69: 722–725, 1982
    OpenUrlCrossRefPubMed
  88. 88.↵
    1. Stubbs JR,
    2. Idiculla A,
    3. Slusser J,
    4. Menard R,
    5. Quarles LD
    : Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD. J Am Soc Nephrol 21: 353–361, 2010
    OpenUrlAbstract/FREE Full Text
  89. 89.↵
    1. Leaf DE,
    2. Wolf M,
    3. Stern L
    : Elevated FGF-23 in a patient with rhabdomyolysis-induced acute kidney injury. Nephrol Dial Transplant 25: 1335–1337, 2010
    OpenUrlCrossRefPubMed
Back to top

In this issue

View Selected Citations (0)
Print
Download PDF
Email Article
Citation Tools
Request Permissions
Forging Forward with 10 Burning Questions on FGF23 in Kidney Disease
Myles Wolf
JASN Sep 2010, 21 (9) 1427-1435; DOI: 10.1681/ASN.2009121293
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section

More in this TOC Section

Cited By...

Similar Articles

Related Articles

  • No related articles found.