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Regional citrate anticoagulation during extracorporeal treatment is used in patients at risk for hemorrhage. We conducted a prospective clinical trial on the effect of large- versus small-dose calcium supplementation during citrate anticoagulated hemodialysis on ionized calcium and intact parathyroid hormone (iPTH). Twenty-five treatments were studied in 25 patients with active bleeding or at risk for hemorrhage. Sixteen patients received large-dose calcium (15 mmol/h), and 9 received small-dose calcium (5 mmol/h) substitution during treatment. Ionized calcium increased in 13 of 16 patients in the large-dose calcium group and decreased in 8 of 9 patients in the small-dose calcium group. Intact PTH decreased by 25% in the large-dose group and increased by 121% in the small-dose group (P = 0.0007 for Δ; P = 0.007 for Δ%). In the 14 patients in whom ionized calcium increased, iPTH decreased. In 10 of 11 patients in whom ionized calcium decreased, iPTH increased. The increase or decrease of ionized calcium was more predictive for changes in iPTH than was the calcium-substitution rate (R2 = 0.5526 versus 0.3962, respectively). We conclude that the behavior of iPTH can be influenced in a predictive manner by adjusting the calcium-substitution rate during treatment.