Calcium Deficiency Reduces Circulating Levels of FGF23

Abstract

Fibroblast growth factor (FGF) 23 inhibits calcitriol production, which could exacerbate calcium deficiency or hypocalcemia unless calcium itself modulates FGF23 in this setting. In Wistar rats with normal renal function fed a diet low in both calcium and vitamin D, the resulting hypocalcemia was associated with low FGF23 despite high parathyroid hormone (PTH) and high calcitriol levels. FGF23 correlated positively with calcium and negatively with PTH. Addition of high dietary phosphorus to this diet increased FGF23 except in rats with hypocalcemia despite high PTH levels. In parathyroidectomized rats, an increase in dietary calcium for 10 days increased serum calcium, with an associated increase in FGF23, decrease in calcitriol, and no change in phosphorus. Also in parathyroidectomized rats, FGF23 increased significantly 6 hours after administration of calcium gluconate. Taken together, these results suggest that hypocalcemia reduces the circulating concentrations of FGF23. This decrease in FGF23 could be a response to avoid a subsequent reduction in calcitriol, which could exacerbate hypocalcemia. 23: 119023: -119723: , 201223: . doi: 10.1681 Fibroblast growth factor (FGF) 23 production is stimulated by both calcitriol and phosphorus intake. FGF23 acts through FGFR-klotho receptors in the kidney to induce phosphaturia, a decrease in 1-a-hydroxylase activity, and an increase in 24-hydroxylase activity. The latter two effects decrease the synthesis and increase the degradation of calcitriol, respectively. 1-4 Parathyroid cells also possess FGFR-klotho receptors, and experimental studies have shown that FGF23 inhibits parathyroid hormone (PTH) production and secretion. [5][6][7] However, in uremic animals, hyperplastic parathyroid glands fail to respond to FGF23 because the expression of FGFR-klotho is downregulated. [7][8][9][10][11] FGF23 effectively increases the output and decreases the input of phosphorus because it directly increases phosphaturia and indirectly decreases intestinal phosphorus absorption by decreasing calcitriol values. However, a conflict will arise if high FGF23 inhibits calcitriol production in a setting of calcium deficiency/hypocalcemia, where high calcitriol is needed to increase intestinal calcium absorption. We have previously observed in parathyroidectomized (PTX) rats with decreased serum J Am Soc Nephrol

Oral Phosphorus Supplementation Secondarily Increases Circulating Fibroblast Growth Factor 23 Levels at Least Partially via Stimulation of Parathyroid Hormone Secretion

“…In addition, hPTH (1-34) treatment only partially recovered the decrease in plasma calcium levels induced by CIN treatment, although hPTH (1-34) administration at the same dose used in the present study has been reported to effectively increase plasma calcium levels in rats (18). These findings suggested that CIN treatment may have decreased plasma FGF23 levels by decreasing plasma calcium levels and by decreasing PTH secretion; thus the inhibitory effects of hypocalcemia on FGF23 secretion may have overwhelmed the stimulatory effect of hPTH (1-34), which supports the proposition by Rodriguez-Ortiz et al (28) that hypocalcemia limits phosphorus-induced FGF23 production. Nemeth et al (16) reported that CIN administration at the same dose used in the present study not only decreased serum PTH levels but also increased serum calcitonin levels in rats.…”

“…In the present study, hPTH (1-34) administration in CIN-treated rats partially recovered the decrease in plasma FGF23 levels, which could be explained by the following two possibilities: first, plasma hPTH (1-34) levels increased in a transient manner, which may not have been sufficient to continuously recover the decrease in plasma FGF23 levels; second, CIN treatment inhibited the increase in plasma FGF23 levels by another mechanism in addition to inhibition of PTH secretion. Rodriguez-Ortiz et al (28) reported that hypocalcemia reduced circulating FGF23 levels. In the present study, plasma calcium levels in CIN-treated rats continued to decrease until 2 h after oral phosphorus administration and afterward, they remained lower for at least 6 h compared with the 0 time point (Fig.…”

A Randomized Study Evaluating Cinacalcet to Treat Hypercalcemia in Renal Transplant Recipients With Persistent Hyperparathyroidism

“…These data, support recent experimental evidence pointing to interactions between calcium and phosphorus in the regulation of FGF-23 production (50,51). Because increases of FGF-23 in renal transplant patients have been correlated with both poor graft function and patient survival (52), it is reassuring that levels remained low.…”

Important abnormalities of bone mineral metabolism are present in patients with coronary artery disease with a mild decrease of the estimated glomerular filtration rate

“…However, the trend towards hypocalcemia as a result of FGF23-mediated suppression of vitamin D activation may increase PTH levels [19,38]. Finally, the presence of diabetes correlated inversely with PTH levels.…”

“…G3a (Mildly to moderately decreased, 45-59), G3b (Moderately to severely decreased, [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44], G4 (Severely decreased [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] and G5 (Kidney failure <15). CKD is defined as either an eGFR <60 ml/min/1.73 m 2 or evidence of kidney injury such as a urinary albumin/creatinine ratio (UACR) >30 mg/g [1].…”