Renal mineral handling in normal rats treated with sevelamer hydrochloride (Renagel), a noncalcemic phosphate binder.
The effects of sevelamer hydrochloride (Renagel); hereafter referred to as sevelamer), a noncalcemic phosphate binder, on renal mineral handling were examined in rats. Normal rats were fed a diet containing 0.3, 1, 3, and 5% sevelamer for 8 days, and serum, urine, and the immunohistochemical localization of the type II Na/Pi cotransporter protein in the kidney were analyzed. Rats treated with 3 or 5% sevelamer showed significant decreases in serum phosphorus (P) and parathyroid hormone (PTH) levels, with no changes in serum calcium (Ca), magnesium (Mg), or 1,25(OH)2D3 levels. Increases were observed in urinary excretions of Ca and Mg associated with a reduction in the PTH level in rats treated with 3 or 5% sevelamer. Rats treated with 1% or higher concentrations of sevelamer showed significant dose-dependent and marked reductions of the urinary P excretion, and the tubular reabsorption of P was maximized to almost 100% in the 5% sevelamer group. The hypophosphaturia in rats treated with 3 or 5% sevelamer was accounted for by the reductions in serum PTH and P per se, and immunohistochemical analysis showed that the expression of type II Na/Pi cotransporter protein was markedly increased at the brush border membranes of the deep and superficial nephrons in rats treated with 5% sevelamer as compared with rats given a normal diet. In conclusion, sevelamer rapidly lowered serum P and PTH levels in normal rats. Sevelamer treatment also produced a marked hypophosphaturia associated with translocation of type II Na/Pi cotransporter protein and increased urinary Ca and Mg excretions by the reduction of PTH.
Nagano
N
N
Laboratory of Pharmaceutical Development, Kirin Brewery Co., Ltd., Gunma, Japan. n-nagano@kirin.co.jp
Miyata
S
S
Obana
S
S
Eto
N
N
Fukushima
N
N
Burke
S K
SK
Wada
M
M
D000284:Administration, Oral; D000818:Animals; D002118:Calcium / Q000652:urine; D004032:Diet; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008274:Magnesium / Q000652:urine; D008297:Male; D010710:Phosphates / Q000097:blood / Q000378:metabolism* / Q000652:urine; D011073:Polyamines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000069603:Sevelamer; D050608:Sodium-Phosphate Cotransporter Proteins; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D027981:Symporters / Q000032:analysis / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000097:blood; D013997:Time Factors
D010710:Phosphates; D011073:Polyamines; D050608:Sodium-Phosphate Cotransporter Proteins; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D027981:Symporters; D013973:Thyrotropin-Releasing Hormone; D000069603:Sevelamer; D008274:Magnesium; D002118:Calcium