Phosphorus is a well-known modulator of renal 1 alpha-hydroxylase activity. In early and moderate renal failure it is proposed that dietary Pi reduction ameliorates secondary hyperparathyroidism through increased circulating levels of calcitriol (i.e, 1 alpha, 25-dihydroxycholecalciferol). To gain further insight into the mechanisms by which a low-Pi diet ameliorates secondary hyperparathyroidism in advanced renal insufficiency, studies were performed in five dogs before and 6 mo after the induction of uremia by 5/6 nephrectomy. Glomerular filtration rate decreased from 69.0 +/- 2.3 to 10.5 +/- 0.5 ml/min, immunoreactive parathyroid hormone (irPTH) increased from 66.0 +/- 8.8 to 321.0 +/- 46 pg/ml, and calcitriol decreased from 39.0 +/- 10.4 to 27.0 +/- 6.2 pg/ml. Thereafter, dietary Pi was decreased gradually every 2 wk from 0.95% to 0.6, 0.45, and 0.3%, respectively. Dietary Ca was reduced from 1.6 to 0.6% to prevent development of hypercalcemia. Ionized Ca (ICa) decreased from 5.4 +/- 0.04 to 5.2 +/- 0.05 mg/dl (P less than 0.02), and plasma Pi decreased from 6.3 +/- 0.7 to 4.7 +/- 0.2 mg/dl (P less than 0.05). Calcitriol remained low (23.3 +/- 4.7 pg/ml). However, irPTH gradually decreased from 321.0 +/- 46.0 to 94.7 +/- 22.9 pg/ml (P less than 0.005). These studies indicate that a decrease in dietary Pi from 0.95 to 0.3% suppressed irPTH by approximately 70%. Reduction of irPTH was observed in the absence of a concomitant increase in levels of ICa or calcitriol. These studies suggest that reduction in dietary Pi in advanced renal insufficiency improves secondary hyperparathyroidism by a mechanism that is independent of the levels of calcitriol or plasma ICa.