Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats.
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.
Nagano
N
N
Pharmaceutical Development Laboratories, Pharmaceutical Research Laboratories and Medical Affairs Section, Pharmaceutical Division, Kirin Brewery Company Limited, Takasaki and Tokyo, Japan. n-nagona@krin.co.jp
Miyata
S
S
Abe
M
M
Kobayashi
N
N
Wakita
S
S
Yamashita
T
T
Wada
M
M
D000225:Adenine / Q000494:pharmacology; D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D002117:Calcitriol / Q000097:blood / Q000502:physiology; D002118:Calcium / Q000097:blood / Q000502:physiology; D003404:Creatinine / Q000097:blood; D004032:Diet; D004435:Eating; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000502:physiology; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood* / Q000502:physiology; D010758:Phosphorus / Q000097:blood* / Q000502:physiology; D011073:Polyamines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000097:blood* / Q000139:chemically induced / Q000503:physiopathology; D000069603:Sevelamer; D013997:Time Factors
D010281:Parathyroid Hormone; D011073:Polyamines; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D000069603:Sevelamer; D003404:Creatinine; D002117:Calcitriol; D000225:Adenine; D002118:Calcium