Long-term, low-dose, cadmium-induced nephropathy with renal osteopathy in ovariectomized rats

To establish an animal model of chronic cadmium nephropathy and osteopathy, we intraperitoneally administered 0.228 mg CdCl2 (Cd) or normal saline (NS) to 52 female Sprague-Dawley (S.D.) rats 3 times a week for 16 months following ovariectomy (OV) or sham surgery (Sham), dividing the animals into three experimental groups (OV-Cd, Sham-Cd and OV-NS). Two groups of male S.D. rats were also administered Cd or NS (22 animals; Male-Cd and Male-NS). Cd-administered rats gained significantly less body weight than NS rats after 16 months of experiments with no signs of emaciation. Serum creatinine levels and Cd contents in the kidney had significantly increased in the Cd-administered rats. OV-Cd rats showed significant decreases in PTH levels and increases in calcium contents in the kidney and other organs. Kidneys of Cd-administered rats showed atrophy, dilatation, and interstitial fibrosis of tubules. Sclerosis and collapse of the glomeruli were observed in the Cd groups with no proliferation in mesangial cells or matrix. The Haversian canal system of the Cd-administered rats disappeared and was replaced by a large quantity of degenerated, necrotic, and restorative tissues. Bone histomorphometric parameters showed that osteoid volume and osteoid surface had significantly increased in the Male-Cd group. In contrast, decreases in bone mass and increases in fibrous tissue were found to be more prominent in the OV-Cd group. Our results have demonstrated for the first time that long-term, low-dose CdCl2 administration to ovariectomized S.D. rats is capable of inducing irreversible nephropathy with osteopathy exhibiting pathological and bone histomorphometric characteristics that are very similar to those of Itai-Itai disease.