Sevelamer hydrochloride reverses parathyroid gland enlargement via regression of cell hypertrophy but not apoptosis in rats with chronic renal insufficiency.
BACKGROUND
Dietary phosphate restriction suppresses parathyroid hormone (PTH) secretion, synthesis, and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI), independently of serum calcium and 1,25(OH)2D3 levels. This study was conducted to examine whether sevelamer hydrochloride (sevelamer), a metal-free phosphate binder, could regress an advanced parathyroid gland (PTG) hyperplasia and enlargement in rats with CRI.


METHODS
Male Sprague-Dawley rats were fed a diet containing adenine for 6 weeks to establish CRI. Normal rats and adenine-treated rats were sacrificed to obtain the PTG (baseline group). The adenine diet was changed to a normal diet or diet containing 1 or 3% sevelamer for another 4 weeks. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of the study, the PTG was weighed and examined histologically.


RESULTS
Adenine-treated rats developed severe CRI with marked elevation of serum phosphorus and PTH. The PTG weight markedly increased with enlarged cell volume (i.e. cell hypertrophy) at baseline. Sevelamer treatment rapidly lowered serum phosphorus and PTH levels within 6 days, and after 4 weeks, reduced the PTG weight by 38% compared to adenine-treated rats at baseline. The reduction in PTG weight was due to regression of cell hypertrophy, but not to decreased cell number by apoptosis. Decreased expression of calcium receptor in the PTG at baseline was partially recovered by the sevelamer treatment.


CONCLUSIONS
The sevelamer treatment can reduce the PTG weight with a reduction in serum PTH levels via regression of cell hypertrophy but not apoptosis in rats with CRI. Reduced PTG function might contribute to the regression of cell hypertrophy.
Nagano
Nobuo
N
Pharmaceutical Development Laboratories, Kirin Brewery Co., Ltd, Takasaki, Japan. n-nagano@kirin.co.jp
Miyata
Sonoe
S
Abe
Megumi
M
Wakita
Sachiko
S
Kobayashi
Nami
N
Wada
Michihito
M
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000097:blood; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006965:Hyperplasia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006984:Hypertrophy / Q000473:pathology; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010280:Parathyroid Glands / Q000187:drug effects / Q000473:pathology*; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood; D011073:Polyamines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000069603:Sevelamer
D010281:Parathyroid Hormone; D011073:Polyamines; D010758:Phosphorus; D000069603:Sevelamer; D002118:Calcium