American Journal of Kidney Diseases
Volume 59, Issue 5 , Pages 607-610, May 2012

Fibroblast Growth Factor 23 and CKD Prognosis

  • Navdeep Tangri, MD, FRCPC

      Affiliations

    • University of Manitoba, Winnipeg, Manitoba, Canada
    • Tufts Medical Center, Boston, Massachussetts
    • Corresponding Author InformationAddress correspondence to Navdeep Tangri, MD, FRCPC, Department of Medicine, Division of Nephrology, Seven Oaks General Hospital, 2PD-13 2300 McPhillips St, Winnipeg MB, R2V 3M3 Canada
    • ,
  • Andrew S. Levey, MD

      Affiliations

    • Tufts Medical Center, Boston, Massachussetts

published online 09 December 2011.

Article Outline

 

Commentary on Isakova T, Xie H, Yang W, et al; for the Chronic Renal Insufficiency Cohort (CRIC) Study Group. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305(23):2432-2439.

Chronic kidney disease (CKD) is a global public health problem with increased risks of death and kidney failure.1 Decreased glomerular filtration rate (GFR) and albuminuria are now recognized as independent risk factors for mortality, cardiovascular disease, and kidney disease outcomes.2, 3, 4, 5 The mechanism for this association appears to be multifactorial, and alterations in mineral metabolism that accompany decreased GFR have been hypothesized to mediate some of this risk.6

Disorders of mineral metabolism occur early in CKD.7 In the last decade, the understanding of bone mineral metabolism in CKD has evolved greatly from a model focusing on regulation of bone mineral metabolism by the kidneys and parathyroid glands (with bone disease as the primary outcome of concern) to a complex interplay also involving regulation by the gut and bone itself (with vascular calcification as an additional important outcome; Fig 1). Similarly, the biomarkers of bone mineral metabolism also have evolved, initially limited to calcium, phosphorus, parathyroid hormone (PTH), and vitamin D, to include other markers, including fibroblast growth factor 23 (FGF-23) and its coreceptor klotho. The latter 2 hormones now appear to be critical in renal phosphorus handling.9

  • View full-size image.
  • Figure 1. 

    Endocrine regulation of phosphate homeostasis. Ten years ago, 2 principal calcium-regulating hormones, 1,25 dihydroxyvitamin D3 (vitamin D) and parathyroid hormone (PTH), were thought to regulate phosphate metabolism. PTH increases vitamin D synthesis in the kidney ①. Vitamin D in turn decreases PTH ②, thereby closing a negative feedback loop. Now the fibroblast growth factor 23 (FGF-23)–klotho system has emerged as the principal phosphate-regulating endocrine axis. FGF-23 is secreted from bone and acts on kidney to decrease vitamin D synthesis ③. Because vitamin D increases FGF-23 expression in bone ④, a negative-feedback loop exists between FGF-23 and vitamin D. FGF-23 also acts on parathyroid to decrease PTH ⑤. Because PTH increases FGF-23 expression ⑥, another negative-feedback loop exists between PTH and FGF-23.

Reproduced and adapted from Kuro-o8 and John et al9 with permission of Macmillan Publishers Ltd and the National Kidney Foundation, respectively.

FGF-23 is a circulating 32-kDa protein that is highly expressed in bone and enters the circulation to regulate phosphorus and vitamin D metabolism. In the kidney, FGF-23 reduces proximal tubular phosphorus absorption. FGF-23 binds to the FGF receptors and requires the cofactor klotho for receptor activation (Fig 1). Additional pathways on the FGF-23–klotho axis include FGF-23 effects on inhibiting vitamin D activation and PTH secretion and klotho effects on increasing renal tubular calcium reabsorption.10 As these pathways have become better understood, there has been strong interest in the association of these biomarkers with prognosis in the healthy adult population and across the spectrum of CKD.

In a recent study published in 2011 in the Journal of the American Medical Association, the CRIC (Chronic Renal Insufficiency Cohort) investigators present their findings exploring the association of FGF-23 with kidney failure and all-cause mortality outcomes.11

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What Does This Important Study Show? 

The CRIC Study and its ancillary, Hispanic CRIC, enrolled 3,939 participants with moderate to severe CKD (estimated GFR [eGFR], 20-70 mL/min/1.73 m2) from 12 centers across the United States in a prospective cohort study. Plasma and urine were collected annually. The present report includes 3,879 participants for whom FGF-23 was assayed from frozen samples obtained at the baseline CRIC visit who were followed up until they reached one of the prespecified outcomes (death or treated kidney failure), were lost to follow-up, or until the censoring date for the present analysis (December 31, 2008).12, 13 The investigators divided the population into quartiles of FGF-23 levels (0-95.7, 95.8-145.1, 145.5-239.1, and >239.2 reference unit [RU]/mL) and used time-to-event analyses to evaluate the association between baseline FGF-23 quartile and the outcomes of death and kidney failure. Cox proportional hazards models were used to examine the association between baseline FGF-23 quartile and the outcomes of death and kidney failure, with multivariable analyses adjusting for demographic factors, eGFR, and other risk factors for CKD progression, including albuminuria, cardiovascular risk factors, use of cardioprotective medications, and alternative markers of bone mineral metabolism, such as calcium, phosphorus, and PTH. Additional sensitivity analyses evaluated interaction terms, adjusted for vitamin D and phosphate-binder use, and used alternative methods of GFR ascertainment, including cystatin C and measured GFR using iothalamate clearance.

The investigators found a strong and independent association of FGF-23 level with all-cause mortality (hazard ratio [HR] of 3.0 [95% confidence interval (CI), 1.8-5.1] comparing highest to lowest quartile and HR of 1.7 [95% CI, 1.6-1.9] for each 1–standard deviation [SD] increase in FGF-23 level). This relationship was not attenuated after adjustment for eGFR, albuminuria, or traditional cardiovascular risk factors and remained robust in sensitivity analyses. Furthermore, FGF-23 level had a stronger association with mortality even compared with fractional excretion of phosphorus (HR of 1.5 [95% CI, 1.3-1.7] for 1.0-SD higher FGF-23 level vs HR of 1.0 [95% CI, 0.9-1.1] for 1.0-SD higher fractional excretion of phosphorus), suggesting the possibility of adverse effects of FGF-23 beyond those mediated by its effect on renal tubular phosphate transport. In contrast, FGF-23 level was not associated with the development of kidney failure in models adjusted for eGFR and albuminuria, although an interaction with eGFR was present, suggesting a stronger association of FGF-23 with the development of kidney failure in participants with baseline eGFR >30 mL/min/1.73 m2.

Strengths of the study included a well-defined contemporary cohort of patients with CKD, as well as adjustment for both conventional markers of bone mineral metabolism and use of medications, including phosphate binders and vitamin D. Additional strengths include sensitivity analyses that show the robustness of the association to alternative measures of GFR. Limitations include a lack of comparison with existing biomarkers of prognosis in CKD, such as troponin T and B-type natriuretic peptide, and lack of data for cause of death.

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How Does This Study Compare With Prior Studies? 

Previous studies examining the role of FGF-23 as a prognostic marker include large studies of patients treated with dialysis or transplant and elderly community-dwelling individuals with preserved kidney function (mean eGFR, 76 mL/min).14, 15, 16 FGF-23 levels in the CRIC Study (median, 146 RU/mL) were significantly lower than the comparable study in the dialysis population (median, 1,752 RU/mL), but still 3- to 5-fold higher than studies of the elderly community-dwelling population (median, 43 RU/mL) and the population with moderate CKD after kidney transplant (median, 28 RU/mL). As a result, the present study11 addresses an important evidence gap for patients with moderate to severe CKD, confirms the independent relationship with FGF-23 and all-cause mortality, and is the first to show the association of FGF-23 with all-cause mortality in CKD independent of eGFR, albuminuria, and traditional cardiovascular risk factors.

The fully adjusted HRs for FGF-23 quartiles observed in the present study11 compare favorably with those observed in previous studies in both the general population (HR, 2.1; 95% CI, 1.4-3.1) and the dialysis population (HR, 5.7; 95% CI, 2.6-12.6). Similar to previous studies, this risk is independent of conventional markers of bone mineral metabolism and use of medications including phosphate binders and vitamin D. In comparison to mortality, the findings of a lack of association of FGF-23 with kidney failure in the CRIC population, along with an interaction suggesting a possible association in patients with moderate CKD (eGFR, 30-60 mL/min/1.73 m2), are novel findings. Although the finding of eGFR as the strongest predictor of kidney failure is consistent with previous studies, the potential utility of FGF-23 as an additional prognostic marker at higher GFRs is intriguing and deserves confirmation.

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What Should Clinicians and Researchers Do? 

The study by Isakova et al11 cements the role of FGF-23 as a potent biomarker for all-cause mortality in patients with CKD. The findings are consistent with previous investigations in the general population and patients with kidney failure, and the relatively high HRs after adjustment suggest an association independent from other well-known causes. These findings highlight the need for additional investigation into the role of FGF-23 and pathways of bone mineral metabolism beyond the kidney as the end organ.

In clinical practice, several questions regarding the role of FGF-23 as a biomarker remain. First, is the association of FGF-23 causal? Given that FGF-23 has multiple biological effects on the kidneys and parathyroid glands, it is tempting to speculate that it may mediate adverse outcomes in CKD, especially through vascular calcification. The CRIC Study cannot provide definitive answers about causality; such questions are best answered by clinical trials. At this time, interventions to decrease FGF-23 levels, such as phosphate binders, are likely to have multiple effects on mediators in this complex interplay. Thus, even a positive clinical trial result may not provide a definitive answer to the mechanism of the relationship of FGF-23 to mortality risk in CKD.

Second, does FGF-23 enable more accurate risk stratification than eGFR, albuminuria, and traditional CVD risk factors? Risk stratification for cardiovascular disease may enable more appropriate and effective application of testing and treatment for cardiovascular disease in CKD. Similarly, risk stratification for kidney disease progression, especially at higher GFRs, may enable more appropriate decision making for the testing and treatment of CKD.17, 18 If FGF-23 enables more accurate risk stratification, it will be important to compare it with other nontraditional biomarkers of mortality, such as troponin T and B-type natriuretic peptide, or alternative exploratory biomarkers, such as ADMA and urinary cyclic guanosine monophosphate.15, 19, 20, 21 These studies are needed to further examine the potential usefulness of FGF-23 in clinical practice. In the absence of net risk reclassification with FGF-23 over existing predictions of all-cause mortality and kidney failure in CKD, FGF-23 may fail to translate to the bedside and may be confined to research laboratories.

Predicting the prognosis of CKD will be important for patients, providers, and health care organizations. Biomarkers with potent independent associations and that can result in actionable changes in predicted risk will have clinical and research utility for patients with CKD. The study by Isakova et al11 highlights FGF-23 as a potent biomarker of CKD prognosis. Examination of the clinical utility of FGF-23 ultimately will be needed before measurement of FGF-23 becomes part of routine clinical practice in CKD.

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Acknowledgements 

Financial Disclosure: Dr Levey has received grants from the National Institutes of Health, National Kidney Foundation, and Amgen. Dr Tangri declares that he has no relevant financial interests.

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References 

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 Originally published online December 9, 2011.

PII: S0272-6386(11)01645-3

doi:10.1053/j.ajkd.2011.11.017

American Journal of Kidney Diseases
Volume 59, Issue 5 , Pages 607-610, May 2012

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