NDT Advance Access published online on July 2, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp323
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As nature did not predict dialysis: what we can learn from FGF23 in end-stage renal disease?
Division of Nephrology, Klinikum Coburg, Coburg, Germany
Correspondence and offprint requests to: Markus Ketteler; E-mail: markus.ketteler{at}klinikum-coburg-de
Keywords: calcification; dialysis; FGF23; hyperphosphataemia; mortality
The fibroblast growth factor 23 (FGF23)/klotho system has raised a lot of attention in the past 10 years. Genetic knockout models demonstrated that failure of this system produces a phenotype of premature ageing and especially a failure to excrete phosphate resulting in significant hyperphosphataemia and vascular calcification [1,2]. FGF23 is synthesized in the bone, and osteocytes increase FGF23 production in response to elevated phosphate and calcitriol [3]. Therefore, FGF23 may be a key adaptive factor preventing early hyperphosphataemia in progressive chronic kidney disease (CKD). In the preterminal phases of CKD, FGF23 may become a valuable biomarker of phosphate load and phosphate exposure, perhaps analogous to the predictive value of HbA1C in the evaluation of diabetes control.
The central target organ of FGF23 appears to be the kidney, where tubular phosphate reabsorption and 1-alpha-hydroxylase expression are suppressed. These features raised the question which role FGF23 might play in dialysis patients (CKD stage 5D), the CKD stage where end-stage kidney failure is firmly established and neither substantial phosphaturic effects can be caused nor an already almost lost calcitriol synthesis can be substantially further suppressed.
The European study by Jean and colleagues in this issue of the journal came to similar results as the US analysis by Gutierrez et al., using a somewhat, but not substantially, different clinical study approach [4,5]. While the latter study had exclusively focussed on incident dialysis patients not on active vitamin D treatment employing a ‘nested’ analysis, the current cross-sectional study reports on a 2-year follow-up of prevalent dialysis patients independent of their active vitamin D therapy. Both investigations found FGF23 serum levels to be extremely high and remaining closely correlated to serum phosphate levels. Thus, FGF23 regulation is apparently regulated in a similar way in dialysis patients as in progressive non-terminal CKD, despite an obvious loss of its intended biological actions on kidney tissue. However, this does not come as a total surprise, since nature could not predict the invention of renal replacement therapy when establishing such a potent antiphosphataemic protection system to protect against premature hyperphosphataemia on the route to renal failure.
The key finding, however, is that in the course of both studies FGF23 has proven to be a strong and independent predictor of mortality, even in serum phosphate ranges which are presently considered relatively safe, at least according to KDOQI target levels for stage CKD 5D (<5.5 mg/dl/<1.78 mmol/l). The apparent link between serum phosphate and FGF23 in this dialysis population raises the question of whether FGF23 may reflect more appropriately the biological harm of individual phosphate levels than the actual phosphate levels themselves (illustrated in Figure 1)? In favour of this theory is the observation by Jean et al. that FGF23 was also apparently related to vascular calcification. Gutierrez et al. just published a link between FGF23 levels and left ventricular hypertrophy in CKD patients [6]—a phenomenon that could potentially be caused by arterial stiffness and increased pulse wave velocity. Alternatively, we should possibly examine whether such enormously elevated FGF23 concentrations, as those present in dialysis patients, are capable of inflicting damage at any tissue sites other than the kidney (such as the myocardium), perhaps by actions on other FGF receptors (FGFR) than on the prototypical dimeric FGFR:klotho receptor.
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There are two observations in the study by Jean et al. that deserve close attention as hypothesis-generating features:
- – In this cohort, patients were undergoing an extended dialysis exposure of 3 x 5 to 3 x 8 h per week. Especially the latter mode generally leads to enhanced phosphate removal often enabling reductions in phosphate binder treatment [7]. Interestingly, there were no significant differences in absolute FGF23 and phosphate serum levels regarding time on dialysis within this study, but potential differences in concomitant phosphate binder dosages were not reported. In the presence of similar mean phosphate levels, the absolute median C-terminal FGF23 levels were higher in the European than in the US study population despite the probability of enhanced dialytic phosphate removal in the former group. Of course, comparisons of different cohorts are almost invalid due to differences in general dialysis exposures (incident versus prevalent), residual diuresis, nutritional status, assay characteristics, racial distribution, etc. Nevertheless, these observations could potentially raise the hypothesis that initial phosphate entry by intestinal absorption may impact more substantially on the counter-regulatory system (FGF23) and perhaps on its related biological harm (soft-tissue calcification) than the achievement of more balanced and lower average phosphate levels by intermittently increasing the phosphate removal. Three times weekly dialysis does not fully reproduce the immediate (probably non-FGF23-related) and continuous (probably FGF23-related) phosphaturic responses of a healthy kidney as Isakova et al. have recently demonstrated [8]. Should this hypothesis gain substantial support, this could mean that binders and diet, as intact kidneys in healthy individuals, might be by far more protective from the biological consequences of phosphate loads than intermittent dialysis-related corrections. In this context, there is some preliminary evidence that effective intestinal phosphate binding indeed suppresses FGF23 secretion [9,10].
- – The observation that warfarin treatment was associated with increased FGF23 levels is very interesting. As a vitamin K antagonist, warfarin inhibits activation (gamma-carboxylation) of vitamin K-dependent proteins among which matrix Gla protein (MGP) is a local vascular calcification inhibitor [11]. This relationship may now suggest a vague and unidentified link between MGP deficiency, FGF23 upregulation and vascular calcification progression, as the authors touch on in their discussion. I would, however, suggest considering an alternative possibility: The osteoblast-secreted protein osteocalcin is another vitamin K-dependent factor, and was recently identified as a further ‘bone-derived’ endocrine factor involved in glucose metabolism, in a way similar to the behaviour of FGF23 on phosphate metabolism [12]. Although in the case of osteocalcin, the differential roles of the uncarboxylated (inactive) versus the gamma-carboxylated (active) isoforms are not entirely understood, warfarin treatment will shift the balance towards undercarboxylation. Given the observations by Jean et al., the hypothesis that a state of osteocalcin activation within the bone may be linked to the regulation of FGF23 at the osteocyte level is potentially tempting; and we would therefore like to urge FGF23 biologists to research this further to either support or exclude such an interrelationship.
- – The observation that warfarin treatment was associated with increased FGF23 levels is very interesting. As a vitamin K antagonist, warfarin inhibits activation (gamma-carboxylation) of vitamin K-dependent proteins among which matrix Gla protein (MGP) is a local vascular calcification inhibitor [11]. This relationship may now suggest a vague and unidentified link between MGP deficiency, FGF23 upregulation and vascular calcification progression, as the authors touch on in their discussion. I would, however, suggest considering an alternative possibility: The osteoblast-secreted protein osteocalcin is another vitamin K-dependent factor, and was recently identified as a further ‘bone-derived’ endocrine factor involved in glucose metabolism, in a way similar to the behaviour of FGF23 on phosphate metabolism [12]. Although in the case of osteocalcin, the differential roles of the uncarboxylated (inactive) versus the gamma-carboxylated (active) isoforms are not entirely understood, warfarin treatment will shift the balance towards undercarboxylation. Given the observations by Jean et al., the hypothesis that a state of osteocalcin activation within the bone may be linked to the regulation of FGF23 at the osteocyte level is potentially tempting; and we would therefore like to urge FGF23 biologists to research this further to either support or exclude such an interrelationship.
Another issue that should be systematically addressed in the future is the impact of treatment with calcitriol or other active vitamin D analogues on FGF23 serum levels, since these compounds may have direct and indirect (by increasing phosphate absorption) stimulatory effects on FGF23 secretion. Jean et al. found a somewhat higher proportion of individuals with active vitamin treatment in their highest quartile of FGF23 levels, while the US study had intentionally excluded this confounder. If FGF23 levels can be directly influenced by this concomitant treatment, the question will however remain whether and in which stage of CKD, FGF23 suppression or stimulation is beneficial or potentially harmful.
These interpretations on the clinical interactions between FGF23 and the mode of phosphate lowering, vitamin K-dependent proteins and active vitamin D use may seem a little far-fetched and are highly speculative. However, if they prove to possess substance they might translate into clinical implications in the years to come. Presently, we are learning progressively more that supports the probability that FSF23 may become a key biomarker in both CKD patients not on dialysis and those in stage 5D. We still need to learn far more about the effects of interventions including different phosphate binder regimens, active vitamin D treatment and diet on FGF23 regulation. We will then need to define absolute cut-off levels of FGF23 concentrations predisposing for mortality risk or representing insufficient phosphate control in the different CKD stages. The dialysis stage is very intriguing with regard to the understanding of FGF23 regulation, since extracorporal replacement of target organ failure was certainly not primarily included in the master plan of evolution.
Conflict of interest statement. None declared.
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References |
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[Abstract/Free Full Text] - Jean G, Terrat JC, Vanel T, et al. High levels of serum Fibroblast Growth Factors (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant. 2009 Apr 25. [epub ahead of print].
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Accepted in revised form: 10. 6.09
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