An animal model was developed to examine the cause of resistance to the calcemic action of PTH in renal failure. Thyroparathyroidectomized (TPTX) rats were repeatedly reinfused with their excreted urine, over a 5-hour period, to produce an acute uremic animal with normal kidneys. Nonuremic controls were infused with equivalent volumes of a simple electrolyte solution. Using this model, we have demonstrated impaired calcemic response to PTH (Lilly Parathyroid Extract, 80 U/100 g) in urine-infused rats compared with electrolyte-infused rats. The final plasma calcium concentrations were 12.0 +/- 0.3 and 14.9 +/- 0.3 mg/dl, respectively (P less than 0.001). The cause of this impaired calcemic response was investigated by reinfusing rats with their own urine that had been pretreated with either activated charcoal or zirconium oxide in two different anionic forms, or urine that had been ultrafiltrated through an Amicon membrane of which the stated molecular-weight cut-off of the smallest pore-size membrane was 500 daltons. It was found that charcoal and ultrafiltration techniques had no effect, whereas the zirconium oxide treatment completely corrected the impaired calcemic response and returned the plasma phosphorus to a concentration similar to that in nonuremic controls. This can be explained by the fact that the principal effect of zirconium oxide on urine is to remove inorganic phosphate. Other groups of TPTX rats given PTH extract were infused with an electrolyte solution containing varying amounts of phosphate up to a maximum similar to the amount that a urine-infused rat would receive. A highly significant inverse relationship was found between the dose of phosphate infused with the electrolyte solution and the measured calcemic response to PTH. This relationship is represented by the following equation: calcium (mg/dl) = 14.84 - 0.139 inorganic phosphate; r = 0.915, P less than 0.001. From these series of studies, we conclude that phosphate retention is the cause of resistance to the calcemic action of PTH extract in this acute uremic model.