Protection from progressive renal failure and hyperparathyroid bone remodeling by WR-2721

In chronic renal failure (CRF), secondary hyperparathyroidism (sHPT) plays a major role in skeletal lesions and also probably in the deterioration of renal functions consecutive to nephrocalcinosis. In this study we tested whether WR-2721 [S-,2-(3-aminopropylamino)-ethylphosphorothioic acid], an inhibitor of parathyroid hormone (PTH) secretion, could prevent the deleterious effects of sHPT at both the bone and kidney level in an animal model of CRF. Rats were either subtotally nephrectomized (NX) or sham-operated (SHAM). They were then pairfed a high phosphorus (1.4%), middle Ca (0.6%) diet. This regimen accelerated the deterioration of renal function in NX rats which displayed signs of severe sHPT in bone (three- to fourfold increase in osteoclast number and resorption surfaces) and kidney (sixfold increase in Ca content) after four weeks. Chronic administration of WR-2721 (20 mg = 0.093 mmol/kg s.c. twice daily) during four weeks completely prevented the progressive elevation of both plasma urea and inorganic phosphate, and the fall of plasma Ca. It also prevented kidney Ca accumulation to the same extent as parathyroidectomy. However, WR-2721 given at this dose only partially prevented the histomorphometric indices of increased bone resorption and formation. This discrepant response suggests that WR-2721 could exert an additional protective effect at the kidney level that might be related to its property of acting as a free radical scavenger. In conclusion, this study suggests that WR-2721 might be a useful compound in CRF, not only because it inhibits PTH secretion, but also because it could protect against the deleterious effect of secondary hyperparathyroidism on kidney functions.