Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats

Abstract

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 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) 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)(2)D(3). 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.

Adenine-induced hyperphosphatemia in a murine model of renal insufficiency

“…increased serum phosphate and FGF23) could be induced in mice with a 4 mg adenine/day gavage without substantial effects on bodyweight loss, and mortality. The increase in serum phosphate in mice receiving an adenine gavage was similar to what has been reported in studies using rats [8]. Increases in kidney weight and serum urea were consistent with renal dysfunction [11,14].…”

“…During the gavage studies, it was noted that the stomachs were enlarged in mice treated with adenine. While it had been previously reported that CKD could alter gastrointestinal motility [33], there was no mention in the animal literature of enlarged stomachs [8,13,14]. The significant enlargement of the stomach caused by adenine supplementation suggested that adenine use in the mouse model might compromise oral administration of test therapies.…”

“…Increases in kidney weight and serum urea were consistent with renal dysfunction [11,14]. The marked increase in blood FGF23 has been previously reported during renal failure [8,15,23]. FGF23 is a bone-derived hormone responsible for the regulation of blood phosphate homeostasis and is responsible for increasing renal excretion of blood phosphate by down regulation of the renal sodium-dependent phosphate co-transporter 2a (NaPi2a), a transporter responsible for the renal resorption of phosphate.…”

“…Furthermore, concurrent active vitamin D supplementation prescribed due to a reduced ability of the kidney to convert vitamin precursors to active vitamin D further exacerbates phosphate absorption [6,7]. Previously, the rat models including the 5/6 nephrectomy and adenineinduced kidney insufficiency rat model have been extensively used for pre-clinical testing in the development of therapies for chronic kidney disease [8][9][10]. The rat adenine-induced kidney insufficiency model is a less invasive refinement over the 5/6 nephrectomy surgical renal insufficiency model [11,12], and was found useful in the development of sevelamer hydrochloride (Sev HCl) as an oral therapy for treatment of hyperphosphatemia [10].…”

“…The rat adenine-induced kidney insufficiency model is a less invasive refinement over the 5/6 nephrectomy surgical renal insufficiency model [11,12], and was found useful in the development of sevelamer hydrochloride (Sev HCl) as an oral therapy for treatment of hyperphosphatemia [10]. Rats fed 0.75% dietary adenine for two weeks developed increased blood phosphate, FGF23, and blood urea nitrogen due to renal insufficiency, appearing sufficient to model human CKD [8,9,11].…”