الفهرس 
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Abstract
Collectively, FGF-23 is a potent negative regulator of circulating phosphate and 1,25-dihydroxyvitamin D (calcitriol; 1,25D) levels.2,5 FGF-23 induces phosphaturia and lowers serum phosphate level through reduction and internalization of the sodium–phosphate cotransporters Npt2a and Npt2c in the kidney proximal tubules. Further, FGF-23 directly suppresses renal 1a-hydroxylase, leading to decreased conversion of 25-hydroxyvitamin D to its active metabolite 1,25D.
Another role of FGF-23 in vitamin D metabolism is to enhance the degradation pathway of vitamin D through stimulation of the 24-hydroxylase. In the context of physiology, more recent studies have also convincingly shown that FGF-23, at least in the short term, directly decreases the transcript level and secretion of parathyroid hormone (pTH). The role of FGF-23 in regulation of pTH and secondary hyperparathyroidism in chronic kidney disease (CKD) is currently under intense investigation.
Whereas the main target of FGF-23 is the kidney, the tissue source of FGF-23 is primarily bone, more specifically osteocytes and osteoblasts. This further underscores the fact that bone, beyond its capacity to store minerals and provide mechanical support, is a highly active endocrine organ. Further, there is robust evidence for the presence of a previously unidentified bone–kidney axis. The interplay between bone and kidney is not farfetched given that the kidney is the main determinant of circulating phosphate levels and actively participates in maintaining calcium homeostasis, providing the skeleton with sufficient minerals to form hydroxyapatite crystals at the mineralization front.
Because FGF-23 holds promise as a biomarker for patient outcome, especially in patients with CKD, it is important to understand its mode of regulation. The most rapid stimuli for FGF-23 expression both in vitro and in vivo is 1,25D, evoking a response in serum FGF-23 level within 3–4 h after intravenous administration. This completes a feedback loop between vitamin D and FGF-23, and FGF-23 can in that sense be viewed as a counter-regulatory hormone for vitamin D. As a result, the decline in vitamin D level that occurs already in the initial phase of CKD can likely be attributed to a rise in FGF-23 rather than a reduced renal mass per se.
FGF-23 production is also promoted by high dietary phosphate intake, as well as chronic hyperphosphatemia, although rapid changes in serum phosphate concentrations may not invoke acute increments in FGF-23. One hypothesis is that FGF-23 responds to the net phosphate balance rather than the serum phosphate level, but experimental data supporting this hypothesis is weak. Further, the complete chain of events from high dietary phosphate intake and hyperphosphatemia to increased FGF-23 synthesis in bone is currently unknown. FGF-23 and Klotho are likely to have important roles in the pathophysiology of secondary hyperparathyroidism.
Although FGF-23 in the short term suppresses pTH secretion, chronically high exposure of FGF-23 may override this effect by lowering the systemic levels of 1,25D and attenuate parathyroid vitamin D receptor signaling. Equally important, it was recently demonstrated that FGF-23 reduces the expression level of Klotho and that parathyroid Klotho expression in surgically removed human parathyroid adenomas declines in parallel with loss of renal function. This is a plausible explanation for the parathyroid FGF-23 ‘resistance’ observed both in CKD patients and in rodent models of experimentally induced renal failure.
In summary, the discovery of FGF-23 and Klotho has led to significant advances in our understanding of mineral metabolism. This knowledge is now gradually being translated into the clinic with many potential implications, including the endorsement of FGF-23 as a predictive biomarker and the possibility of FGF-23/Klotho as a novel therapeutic target.
Given its central role in regulating mineral metabolism, the obvious question arises: How important is FGF-23 clinically? In early CKD, FGF-23 appears to be beneficial, compensating for reduced phosphate excretory capacity by increasing fractional excretion of phosphate. Although phosphate retention is also a stimulus for pTH secretion, in early-stage CKD the rise in FGF-23 is more pronounced than that of pTH, possibly because of the inhibitory effects of FGF-23 on pTH. A trade-off of the increase of FGF-23 may be a reduction in levels of 1,25D by the mechanism described above.
As CKD progresses, the efficacy of FGF-23 to induce phosphaturia declines, due to at least two mechanisms. First, the loss of functioning nephrons reduces the amount of phosphate being ultrafiltrated; second, lowered renal Klotho expression dismantles the FGF-23 receptor, leading to higher phosphate reabsorption per nephron. For these reasons it is expected that in advanced CKD, FGF-23 could be an indicator for dismal outcome. Indeed, this has been shown for more advanced CKD, where FGF-23 independent predicted progression of disease. The fact that correcting for phosphate level, pTH, and vitamin D use did not mitigate predictive value of FGF-23 for dismal outcome is remarkable, because these parameters were thought to be in the same causal pathway as FGF-23. This could mean that FGF-23 is a sensitive marker for phosphate burden, or induces harm itself. In support for the first hypothesis, FGF-23 has, in large observational studies of elderly subjects with normal or only mildly impaired renal function, been associated with vascular dysfunction, total atherosclerotic burden, and left ventricular hypertrophy.
Further, FGF-23 is also a predictor of fracture risk in this population, another central feature of CKD–mineral and bone disorder (CKD–MBD). Arguments for the latter come from a recent study indicating that FGF-23 influences flowmediated vasodilation in CKD stage 3 and 4 patients. Additional arguments, albeit indirect, come from recent research indicating FGF-23 as a factor associated with left ventricular mass index independent from brain natriuretic peptide,myocardial performance, and coronary artery disease.
If FGF-23 indeed turns out to be either a sensitive biomarker of phosphate load, or has some different pathological effect in advanced stages of CKD, the next clinical question would be: Is it modifiable? from a theoretical point of view, options to lower FGF-23 would be to reduce levels of active vitamin D, pTH, and phosphate burden. Indeed, parathyroidectomy has been shown to induce a significant decline in FGF-23, possibly because of the direct effect of pTH on FGF-23 production.
Lowering dietary phosphate intake decreases FGF-23 in healthy volunteers with a lag time, but this approach is not likely to be sufficient in CKD. The use of phosphate binders has shown inconsistent results as FGF-23-lowering agents. Sevelamer declined FGF-23 in a dose-dependent manner in an experimental model of uremia, and this was confirmed clinically after 6 weeks of treatment. Use of calcium-based binder therapy did not change FGF-23 significantly in that study. These findings were confirmed in a cohort of 72 hemodialysis patients followed up for 1 year. Use of lanthanum carbonate, however, while significantly reducing 24-h urine phosphate excretion, indicating adequate phosphate binding, did not change FGF-23. This absence of effect of lanthanum carbonate on FGF-23 in this study, however, could have been caused by a too short study period of two weeks only, since more time may be required for FGF-23 to slow down. Indeed, in a very recent study, extended use of lanthanum carbonate in an otherwise comparable study population did significantly suppress FGF-23 by almost 25%. Lowering levels of 1,25D in CKD as a way to decline FGF-23 is not an attractive option for obvious reasons.
Currently, there is no evidence supporting the fact that FGF-23 is a modifiable risk factor that leads to improvement of clinical outcomes such as mortality. prospective trials are underway that study changes in vascular function after FGF-23-targeted interventions. A critical question is whether FGF-23 is purely a biomarker of phosphate exposure or if it has ‘off-target’ effects directly contributing to vascular toxicity. If FGF-23 levels are reduced by means of improving phosphate control, it will be difficult to analyze whether changes in outcomes are related to a more stringent phosphate control or a consequence of a lower FGF-23 level per se. Another option that could shed light on this question would be to intervene at the level of FGF-23-producing cells, either osteocytes in bone or ectopic production from bone cells in the vessel wall in the presence of calcified arterial lesions, by using FGF-23 blocking agents or upstream transcriptional inhibitors of FGF-23. from the convincing epidemiological association between FGF-23 and mortality in dialysis patients, an enigma emerges: How is it possible that a hormone such as FGF-23 has such an impact on outcome, while its main target organ the kidney is non-functioning? Of course, the parathyroid is another target for FGF-23; however, in CKD, pTH suppression by FGF-23 is abolished by parathyroid resistance. Although it is likely that all FGF-23 actions require the presence of the FGF receptor 1c and membrane Klotho, theoretically, other tissues expressing Klotho and FGF receptor 1c might be unidentified targets for FGF-23.
Recently, both Klotho and FGF receptor-1 were shown to be present in human aortic smooth muscle cell, but at present it is unclear whether this is membrane-bound or soluble Klotho, and whether actual signal transduction by FGF-23 can occur at this site. Nevertheless, the arterial wall and cardiomyocytes as target tissues for FGF-23 action is an attractive concept, given the central role of cardiovascular disease in CKD-associated morbidity. Alternatively, indirect effects of FGF-23 on the arterial wall are also plausible. These could be mediated by phosphate itself or by a reduction in Klotho level, given that FGF-23 suppresses Klotho, and recent data suggest that it is implicated in the process of arterial calcification.