Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats
2006; Elsevier BV; Volume: 69; Issue: 3 Linguagem: Inglês
10.1038/sj.ki.5000020
ISSN1523-1755
AutoresNobuo Nagano, Sonoe Miyata, Masahiko Abe, Nobuhiko Kobayashi, Sachiko Wakita, Takefumi Yamashita, M. Wada,
Tópico(s)Genetic Syndromes and Imprinting
ResumoPhosphorus directly controls parathyroid hormone (PTH) synthesis and secretion. Serum levels of the novel phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), are positively correlated with hyperphosphatemia in patients with chronic renal insufficiency (CRI). We proposed that changes in serum PTH and FGF23 levels might be associated with changes in serum phosphorus levels caused by the phosphate binder sevelamer hydrochloride (sevelamer, i.e. crosslinked poly[allylamine hydrochloride]). Rats were fed a diet containing adenine for 4 weeks to establish CRI. Animals were then offered either a normal diet or a diet containing 1 or 3% sevelamer for 8 weeks continuously, or intermittently with sevelamer diet or a normal diet offered for alternating 2-week periods. Changes in the serum levels of phosphorus, calcium, PTH, FGF23, and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) were monitored over time. Adenine-treated rats developed severe CRI, with markedly elevated serum levels of phosphorus, PTH and FGF23, and reduced levels of serum 1,25(OH)2D3. Continuous treatment with sevelamer suppressed these increases throughout the study period. Serum phosphorus, PTH, and FGF23 levels decreased rapidly when sevelamer treatments commenced and recovered rapidly once they were discontinued. However, the changes in serum FGF23 levels began after the onset of changes in serum phosphorus and PTH levels. In conclusion, circulating PTH, and FGF23 levels can be promptly manipulated through the control of serum phosphorus levels. Moreover, phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under conditions of CRI. Phosphorus directly controls parathyroid hormone (PTH) synthesis and secretion. Serum levels of the novel phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), are positively correlated with hyperphosphatemia in patients with chronic renal insufficiency (CRI). We proposed that changes in serum PTH and FGF23 levels might be associated with changes in serum phosphorus levels caused by the phosphate binder sevelamer hydrochloride (sevelamer, i.e. crosslinked poly[allylamine hydrochloride]). Rats were fed a diet containing adenine for 4 weeks to establish CRI. Animals were then offered either a normal diet or a diet containing 1 or 3% sevelamer for 8 weeks continuously, or intermittently with sevelamer diet or a normal diet offered for alternating 2-week periods. Changes in the serum levels of phosphorus, calcium, PTH, FGF23, and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) were monitored over time. Adenine-treated rats developed severe CRI, with markedly elevated serum levels of phosphorus, PTH and FGF23, and reduced levels of serum 1,25(OH)2D3. Continuous treatment with sevelamer suppressed these increases throughout the study period. Serum phosphorus, PTH, and FGF23 levels decreased rapidly when sevelamer treatments commenced and recovered rapidly once they were discontinued. However, the changes in serum FGF23 levels began after the onset of changes in serum phosphorus and PTH levels. In conclusion, circulating PTH, and FGF23 levels can be promptly manipulated through the control of serum phosphorus levels. Moreover, phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under conditions of CRI. Hyperphosphatemia is a major complication in hemodialysis patients and plays a key role in the pathogenesis of secondary hyperparathyroidism (2HPT).1.Slatopolsky E. Dusso A. Brown A.J. The role of phosphorus in the development of secondary hyperparathyroidism and parathyroid cell proliferation in chronic renal failure.Am J Med Sci. 1999; 317: 370-376Crossref PubMed Google Scholar, 2.Rodriguez M. Direct effect of phosphate on parathyroid function.Nephrol Dial Transplant. 1999; 14: 70-72Crossref PubMed Scopus (9) Google Scholar, 3.Silver J. Kilav R. Naveh-Many T. Mechanisms of secondary hyperparathyroidism.Am J Physiol Renal Physiol. 2002; 283: F367-F376Crossref PubMed Scopus (149) Google Scholar It is now widely accepted that phosphate directly stimulates parathyroid hormone (PTH) secretion and synthesis, as well as parathyroid cell proliferation, independently of calcium and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Conversely, restricting phosphate by means of a low phosphorus diet or phosphate-binder treatment can reverse hyperparathyroidism. Fibroblast growth factor 23 (FGF23) was recently identified as a causative factor in phosphate-wasting disorders, such as tumor-induced osteomalacia, autosomal dominant hypophosphatemic rickets and X-linked hypophosphatemic rickets.4.Schiavi S.C. Kumar R. The phosphatonin pathway: new insights in phosphate homeostasis.Kidney Int. 2004; 65: 1-14Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Marked elevations of serum FGF23 levels have been positively correlated with serum levels of phosphorus, calcium and PTH in patients with end-stage renal disease.5.Larsson T. Nisbeth U. Ljunggren Ö et al.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. 2003; 64: 2272-2279Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar, 6.Imanishi Y. Inaba M. Nakatsuka K. et al.FGF-23 in patients with end-stage renal disease on hemodialysis.Kidney Int. 2004; 65: 1943-1946Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 7.Shigematsu T. Kazama J.J. Yamashita T. et al.Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency.Am J Kidney Dis. 2004; 44: 250-256Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, 8.Sato T. Tominaga Y. Ueki T. et al.Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism.Am J Kidney Dis. 2004; 44: 481-487Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar Interestingly, total parathyroidectomy (PTx) reduced serum phosphorus levels and simultaneously decreased serum FGF23 levels in patients on dialysis.8.Sato T. Tominaga Y. Ueki T. et al.Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism.Am J Kidney Dis. 2004; 44: 481-487Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar In healthy subjects, serum FGF23 levels decreased on a low phosphorus diet and increased with oral phosphorus load,9.Ferrari S.L. Bonjour J.P. Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men.J Clin Endocrinol Metab. 2005; 90: 1519-1524Crossref PubMed Scopus (403) Google Scholar although an alternative study reported that FGF23 levels were not affected by oral phosphorus deprivation or loading.5.Larsson T. Nisbeth U. Ljunggren Ö et al.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. 2003; 64: 2272-2279Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar In an animal study, a high phosphorus diet increased serum FGF23 levels in 5/6 nephrectomized rats.10.Saito H. Maeda A. Ohtomo S. et al.Circulating FGF-23 is regulated by 1α,25-dihydroxyvitamin D3 and phosphorus in vivo.J Biol Chem. 2005; 280: 2543-2549Crossref PubMed Scopus (355) Google Scholar On the other hand, the administration of recombinant FGF23 slightly decreased serum PTH levels in normal mice and reduced serum phosphorus and 1,25(OH)2D3 levels in rats that underwent PTx.11.Shimada T. Hasegawa H. Yamazaki Y. et al.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.J Bone Miner Res. 2004; 19: 429-435Crossref PubMed Scopus (1243) Google Scholar Conversely, the administration of 1,25(OH)2D3 increased serum FGF23 levels in mice11.Shimada T. Hasegawa H. Yamazaki Y. et al.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.J Bone Miner Res. 2004; 19: 429-435Crossref PubMed Scopus (1243) Google Scholar and thyroparathy-roidectomized rats without correlation with serum phosphorus levels.10.Saito H. Maeda A. Ohtomo S. et al.Circulating FGF-23 is regulated by 1α,25-dihydroxyvitamin D3 and phosphorus in vivo.J Biol Chem. 2005; 280: 2543-2549Crossref PubMed Scopus (355) Google Scholar Thus, it remains unclear whether phosphorus, calcium, PTH, 1,25(OH)2D3 or an alternative factor is directly responsible for the marked elevation of circulating FGF23 levels under chronic renal insufficiency (CRI) conditions. Sevelamer hydrochloride (sevelamer, crosslinked poly[allylamine hydrochloride]) is a metal-free phosphate-binding polymer that is marketed for the treatment of hyperphosphatemia in patients on dialysis. Previously, we demonstrated beneficial protective effects of sevelamer on parathyroid cell proliferation,12.Nagano N. Miyata S. Obana S. et al.Sevelamer hydrochloride, a calcium-free phosphate binder, inhibits parathyroid cell proliferation in partially nephrectomized rats.Nephrol Dial Transplant. 2003; 18: iii81-iii85PubMed Google Scholar parathyroid hyperplasia,13.Nagano N. Miyata S. Onaba S. et al.Sevelamer hydrochloride (Renagel®), a non-calcaemic phosphate binder, arrests parathyroid gland hyperplasia in rats with progressive chronic renal insufficiency.Nephrol Dial Transplant. 2001; 16: 1870-1878Crossref PubMed Scopus (30) Google Scholar renal functional deterioration,14.Nagano N. Miyata S. Obana S. et al.Sevelamer hydrochloride, a phosphate binder, protects against deterioration of renal function in rats with progressive chronic renal insufficiency.Nephrol Dial Transplant. 2003; 18: 2014-2023Crossref PubMed Scopus (36) Google Scholar and high-turnover bone lesions15.Katsumata K. Kusano K. Hirata M. et al.Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats.Kidney Int. 2003; 64: 441-450Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar in rats with progressive CRI, in addition to its lowering effects on serum phosphorus and PTH levels and on urinary phosphorus excretion in normal rats16.Nagano N. Miyata S. Obana S. et al.Renal mineral handling in normal rats treated with sevelamer hydrochloride (Renagel®), a noncalcemic phosphate binder.Nephron. 2001; 89: 321-328Crossref PubMed Scopus (14) Google Scholar and rats with CRI.12.Nagano N. Miyata S. Obana S. et al.Sevelamer hydrochloride, a calcium-free phosphate binder, inhibits parathyroid cell proliferation in partially nephrectomized rats.Nephrol Dial Transplant. 2003; 18: iii81-iii85PubMed Google Scholar, 13.Nagano N. Miyata S. Onaba S. et al.Sevelamer hydrochloride (Renagel®), a non-calcaemic phosphate binder, arrests parathyroid gland hyperplasia in rats with progressive chronic renal insufficiency.Nephrol Dial Transplant. 2001; 16: 1870-1878Crossref PubMed Scopus (30) Google Scholar, 14.Nagano N. Miyata S. Obana S. et al.Sevelamer hydrochloride, a phosphate binder, protects against deterioration of renal function in rats with progressive chronic renal insufficiency.Nephrol Dial Transplant. 2003; 18: 2014-2023Crossref PubMed Scopus (36) Google Scholar, 15.Katsumata K. Kusano K. Hirata M. et al.Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats.Kidney Int. 2003; 64: 441-450Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Excess dietary adenine is converted to 2,8-dihydroxyadenine, which is significantly less soluble in water, and impairs renal function by forming intratubular and interstitial precipitates of acicular crystals.17.Yokozawa T. Oura H. Koizumi F. 2,8-Dihydroxyadenine urolithiasis induced by dietary adenine in rats.Jpn J Nephrol. 1985; 27: 371-378Google Scholar, 18.Yokozawa T. Zheng P.D. Oura H. et al.Animal model of adenine-induced chronic renal failure in rats.Nephron. 1986; 44: 230-234Crossref PubMed Scopus (280) Google Scholar Severe CRI, accompanied by hyperphosphatemia and 2HPT, is seen in adenine-treated rats.15.Katsumata K. Kusano K. Hirata M. et al.Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats.Kidney Int. 2003; 64: 441-450Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar In the present study, we examined how serum PTH and FGF23 levels were affected by manipulating serum phosphorus levels through the intermittent administration of sevelamer in adenine-treated rats. Body weight gain was reduced in the adenine-treated rats compared to that in the normal control group (Figure 1a). The sevelamer treatments did not significantly affect body weight during the study, although a slight increase was observed in the 3% sevelamer continuous-treatment group. The mean food intake volumes in g/day were as follows: 25.4±0.47 for the normal control group; 12.1±0.63 for the disease control group; 13.3±0.46 for the 1% sevelamer continuous-treatment group; 15.2±0.61 for the 3% sevelamer continuous-treatment group; 12.6±0.50 for the 1% sevelamer intermittent-treatment group; and 14.3±0.69 for the 3% sevelamer intermittent-treatment group. The blood urea nitrogen (BUN) and serum creatinine levels increased rapidly during the 4 weeks of adenine treatment (days -28 to -1; Figure 1b and c). After the end of the adenine treatment period, the BUN, and serum creatinine levels remained high, although they began to decrease gradually towards the end of the study. The sevelamer treatments had no significant effect on the BUN and serum creatinine levels during the study, regardless of whether it was given continuously or intermittently. In the disease control group, the serum phosphorus levels increased rapidly during the adenine treatment (days -28 to -1), reached a maximum at the end of this period and showed a slight decrease towards the end of the study (Figure 2). At 1 day after switching from the adenine diet to the 1 or 3% sevelamer diets (day 1), the serum phosphorus levels decreased rapidly to around the normal control levels. In the 3% sevelamer groups, further decreases in serum phosphorus levels were observed both 3 and 7 days after the treatment commenced (days 3 and 7), while in the 1% sevelamer groups, normal levels were maintained. Serum phosphorus levels in the 1% sevelamer continuous-treatment group remained similar to those of the normal control group, while in the 3% sevelamer continuous group, the levels were below those in the normal controls until the end of the study (Figure 2a). In the 3% sevelamer intermittent-treatment group, the serum phosphorus levels rapidly returned to normal control levels on day 15 (i.e., 1 day after the normal diet started), increased above the disease control levels on day 17 (i.e., 3 days after the normal diet started) and then gradually decreased (Figure 2b). The second cycle of treatment with sevelamer (days 28–42) suppressed serum phosphorus levels, whereas discontinuation of the treatment (day 42) caused them to begin to rise again. Slight hypercalcemia followed by slight hypocalcemia was observed in the disease control group compared to the normal control group (Figure 3). Serum calcium levels rapidly increased within 3 days of the start of the 1 and 3% sevelamer treatments, and the continuous-treatment groups maintained relatively high levels throughout the study (Figure 3a). Three days after switching from the sevelamer diet to the normal diet, marked reductions in serum calcium levels were observed in the intermittent-treatment groups (days 17 and 45) (Figure 3b). In the disease control group, serum PTH levels rose progressively and dramatically throughout the study (Figure 4). By contrast, once the 1% sevelamer treatments had commenced, the serum PTH levels began to decrease gradually, while the 3% sevelamer treatments caused the serum PTH levels to decrease rapidly to around the normal control levels just 1 day after they commenced (day 1), and caused further decreases below the normal control levels until day 13. The 1 and 3% sevelamer continuous treatments continued to reduce serum PTH levels dose-dependently until the end of the study (Figure 4a). In particular, the 3% sevelamer continuous treatment kept the serum PTH levels below the normal control levels during the early part of the study. At 1 day after switching from the sevelamer diet to the normal diet, the serum PTH levels rapidly and markedly increased, especially in the 3% sevelamer intermittent-treatment group (day 15) (Figure 4b). The second intermittent treatments of sevelamer (days 28–42) decreased the serum PTH levels, and discontinuation of these treatments (day 42) caused the serum PTH levels to begin to rise again; the magnitude of the changes was greater in the 3% sevelamer intermittent-treatment group than in the 1% group. In the disease control group, the serum FGF23 levels progressively and dramatically increased, reaching a maximum on day 15 and then decreasing gradually (Figure 5). Even the high dose (3%) sevelamer treatments did not affect serum FGF23 levels 1 day after they were initiated (day 1), and the levels decreased gradually between days 3 and 13. In the 1 and 3% sevelamer continuous-treatment groups, serum FGF23 levels continued to decrease dose-dependently until the end of the study (Figure 5a). In the high dose (3%) sevelamer intermittent-treatment group, there was no effect on the serum FGF23 levels 1 day after switching from the sevelamer diet to the normal diet on day 15, but it began to rise from day 17 onwards (Figure 5b). The second treatments with sevelamer (days 28–42) decreased the serum FGF23 levels and discontinuation of treatments (day 42) caused the levels to begin to rise again; the magnitude of the changes was greater in the 3% sevelamer intermittent-treatment group than in the 1% group. During the adenine treatment (days -28 to -1), the serum 1,25(OH)2D3 levels decreased markedly, reaching values close to zero, and then increased slightly as the study progressed (Figure 6). The sevelamer treatments had no significant effect on serum 1,25(OH)2D3 levels during the study. Rats fed with adenine were chosen as an animal model for CRI in this study because it is simple to produce and shows relatively stable, long-lasting, and severe uremia, with hyperphosphatemia and 2HPT, even after the discontinuation of adenine feeding.15.Katsumata K. Kusano K. Hirata M. et al.Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats.Kidney Int. 2003; 64: 441-450Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Intermittent sevelamer treatments were used to manipulate the circulating phosphorus levels dynamically, and the concomitant changes in serum PTH and FGF23 levels were monitored. Prior to this study, a lag period between the start of sevelamer treatment and the onset of the reduction of serum phosphorus levels was predicted due to the mobilization of phosphate from the bones and intracellular pools. However, serum phosphorus levels were found to decrease 1 day after the start of the sevelamer treatments. Conversely, a rise in the serum phosphorus levels was observed 1 day after the sevelamer treatments were discontinued and they returned to their original levels within 3 days. At 3 days after the discontinuation of the high dose (3%) sevelamer treatment, a rebound phenomenon (i.e., marked hyperphosphatemia) was observed, particularly on day 17. This suggested that an intestinal phosphate absorption system, probably comprised of Na/Pi cotransporter type IIb (Na/Pi IIb), might have been upregulated during the phosphorus restriction caused by 2-week sevelamer treatment. It is of some interest that phosphate depletion might still result in the upregulation of Na/Pi IIb even under conditions of very severe CRI. The sevelamer treatments increased the serum calcium levels dose-dependently. The increased serum calcium levels are partly dependent on the reduction of serum phosphorus levels induced by sevelamer treatment (i.e., a counter-ion effect). In addition to this mechanism, we reported previously that sevelamer treatment decreased fecal calcium excretion and increased intestinal calcium absorption in a balance study with normal rats.19.Nagano N. Obana S. Miyata S. et al.Mechanism of the cholesterol-lowering effect of sevelamer hydrochloride, a novel phosphate binder.J Jpn Soc Dial Ther. 2003; 36: 47-54Crossref Google Scholar Thus, it is also likely that intestinal phosphate binding by sevelamer might increase the concentration of free calcium ions, resulting in increased intestinal calcium absorption. Furthermore, the marked reduction in serum PTH levels by sevelamer might decrease the bone capacity to buffer an intestinal extra calcium load and facilitate the elevation of serum calcium levels. Interestingly, serum PTH levels continued to rise progressively during the study in adenine-treated rats receiving the normal diet (disease control group), despite stable or only minor decreases in levels of serum creatinine, phosphorus and calcium levels and the minor increase in 1,25(OH)2D3 levels. This indicated a progressive development of parathyroid hyperfunction, independent of renal function, calcium, phosphorus and 1,25(OH)2D3 levels, suggesting that long-lasting uremic conditions per se can promote 2HPT. The elevated serum PTH levels rapidly decreased when the sevelamer treatments commenced, and returned to their original levels soon after discontinuation of the treatments. Along with the rapid recovery of serum phosphorus levels after the discontinuation of the sevelamer treatments, these findings support that clinical treatment with a phosphate binder should not be discontinued abruptly. The time course of the changes in serum PTH levels was similar to that for serum phosphorus levels. An in vitro study demonstrated previously that elevated phosphate concentrations in the culture media increased PTH secretion from the rat parathyroid gland within 3 h.20.Slatopolsky E. Finch J. Denda M. et al.Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro.J Clin Invest. 1996; 97: 2534-2540Crossref PubMed Scopus (439) Google Scholar Another in vivo study using normal dogs showed that continuous intravenous infusion of phosphate increased serum PTH levels within 90 min under the serum calcium clamp conditions.21.Estepa J.C. Aguilera-Tejero E. Lopez I. et al.Effect of phosphate on parathyroid hormone secretion in vivo.J Bone Miner Res. 1999; 14: 1848-1854Crossref PubMed Scopus (63) Google Scholar Although we were unable to examine the hourly changes in serum parameters, the onset of the changes in serum PTH levels seemed likely to follow those of the serum phosphorus levels. These observations also support a direct and acute effect of phosphate on PTH secretion in vivo, although part of the serum PTH changes could be explained by the serum calcium changes induced by the sevelamer treatments. A marked elevation in serum FGF23 levels was observed in the adenine-treated rats, which was consistent with previous reports of patients and animals with CRI.5.Larsson T. Nisbeth U. Ljunggren Ö et al.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. 2003; 64: 2272-2279Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar, 6.Imanishi Y. Inaba M. Nakatsuka K. et al.FGF-23 in patients with end-stage renal disease on hemodialysis.Kidney Int. 2004; 65: 1943-1946Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 7.Shigematsu T. Kazama J.J. Yamashita T. et al.Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency.Am J Kidney Dis. 2004; 44: 250-256Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, 8.Sato T. Tominaga Y. Ueki T. et al.Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism.Am J Kidney Dis. 2004; 44: 481-487Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 10.Saito H. Maeda A. Ohtomo S. et al.Circulating FGF-23 is regulated by 1α,25-dihydroxyvitamin D3 and phosphorus in vivo.J Biol Chem. 2005; 280: 2543-2549Crossref PubMed Scopus (355) Google Scholar FGF23 mRNA is present in many tissues, including the thymus, brain, bone, thyroid/parathyroid gland and heart.22.Yamashita T. Yoshioka M. Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain.Biochem Biophys Res Comm. 2000; 277: 494-498Crossref PubMed Scopus (399) Google Scholar, 23.Shimada T. Mizutani S. Muto T. et al.Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.Proc Natl Acad Sci USA. 2001; 98: 6500-6505Crossref PubMed Scopus (1120) Google Scholar, 24.Liu S. Guo R. Simpson L.G. et al.Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX.J Biol Chem. 2003; 278: 37419-37426Crossref PubMed Scopus (386) Google Scholar According to a recent study,25.Nakanishi S. Kazama J.J. Nii-Kono T. et al.Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients.Kidney Int. 2005; 67: 1171-1178Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar abundant FGF23 expression in the bone seems to be conclusive, but expressions in some other organs are still controversial. In addition, it remains unclear as to which of these organs makes the largest contribution to the significantly elevated circulating FGF23 levels in CRI. Furthermore, the presence of FGF23 in urine has suggested that increased FGF23 levels in CRI are partly due to a decreased clearance of FGF23 by the kidney.5.Larsson T. Nisbeth U. Ljunggren Ö et al.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. 2003; 64: 2272-2279Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar However, the present result that the intermittent sevelamer treatment drastically changed serum FGF23 levels without affecting renal function clearly indicates that declining renal clearance of FGF23 is not solely responsible for its upregulation. This result may also suggest a hypothesis that the FGF23 response is physiologically relevant rather than a nonimportant consequence of CRI. In addition to the renal tubular lesions in adenine-treated rats, it is considered that marked elevation of serum FGF23 levels partly contributes to the depletion of serum 1,25(OH)2D3 levels. At present, with the exception of the potent downregulation of renal 25-hydroxyvitamin D3-1 alpha-hydroxylase and Na/Pi IIa in physiological conditions, the functional significance of the elevated serum FGF23 levels under CRI conditions remains unclear. However, the present study is the first to show that phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under CRI conditions. Similar to the influences on serum PTH levels, initiating and discontinuing the sevelamer treatments decreased and increased the serum FGF23 levels. However, the onset of the changes in serum FGF23 levels showed a lag period (at least 1–3 days), and followed the changes in serum phosphorus and PTH levels; serum FGF23 levels were not altered 1 day after the sevelamer treatments began or ended. Similar observations were reported in healthy human subjects, whose serum FGF23 levels decreased on a low phosphorus diet and then increased with an increased oral intake; it took 5–7 days to detect any significant changes in these individuals.9.Ferrari S.L. Bonjour J.P. Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men.J Clin Endocrinol Metab. 2005; 90: 1519-1524Crossref PubMed Scopus (403) Google Scholar In addition, a high phosphorus diet was shown to enhance, and a low phosphorus diet to inhibit, the elevation of serum FGF23 levels in 5/6 nephrectomized rats, although this result was obtained after 4 weeks of the dietary treatment.10.Saito H. Maeda A. Ohtomo S. et al.Circulating FGF-23 is regulated by 1α,25-dihydroxyvitamin D3 and phosphorus in vivo.J Biol Chem. 2005; 280: 2543-2549Crossref PubMed Scopus (355) Google Scholar Taken together, these findings suggest that serum FGF23 is predominantly regulated by phosphorus, although it is unclear why a lag period occurs. The regulatory mechanisms for FGF23 production and/or secretion should be clarified. It is possible that serum PTH levels might determine circulating FGF23 levels, because the PTx can reduce FGF23 levels in patients on dialysis.8.Sato T. Tominaga Y. Ueki T. et al.Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism.Am J Kidney Dis. 2004; 44: 481-487Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar However, despite complete surgical ablation of the parathyroid glands, the magnitude of the changes in serum FGF23 levels was relatively small and the serum phosphorus levels simultaneously decreased in this report. Further studies using PTx rats should be conducted in order to exclude the PTH-dependent regulation of FGF23. The administration of FGF23 lowers serum 1,25(OH)2D3 levels, and 1,25(OH)2D3 reciprocally increases FGF23 levels in mice11.Shimada T. Hasegawa H. Yamazaki Y. et al.FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.J Bone Miner Res. 2004; 19: 429-435Crossref PubMed Scopus (1243) Google Scholar and rats in the absence of the parathyroid gland,10.Saito H. Maeda A. Ohtomo S. et al.Circulating FGF-23 is regulated by 1α,25-dihydroxyvitamin D3 and phosphorus in vivo.J Biol Chem. 2005; 280: 2543-2549Crossref PubMed Scopus (355) Google Scholar suggesting that 1,25(OH)2D3, as well as phosphate, regulates circulating FGF23 levels. However, the sevelamer treatment decreased serum FGF23 levels without influencing serum 1,25(OH)2D3 levels, indicating that the changes in serum FGF23 levels observed in this study were independent of 1,25(OH)2D3. Another possibility remained that serum calcium might have been involved in the regulation and determination of circulating FGF23 levels in this study. Thus, further research will be necessary to determine which factor is directly responsible for the significantly elevated circulating FGF23 levels under CRI conditions. However, the present study suggests that serum phosphorus levels predominantly determine the circulating FGF23 levels. Elevated circulating PTH and FGF23 levels were lowered rapidly by the initiation of phosphate-binder treatment, even under severe 2HPT conditions. However, after discontinuation of the phosphate-binder treatment, the PTH and FGF23 levels recovered promptly. This is the first report showing that phosphate-binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under CRI conditions.
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