Renal and systemic acid-base effects of the chronic administration of hypercalcemia-producing agents: Calcitriol, PTH, and intravenous calcium

Balance studies were performed in dogs to characterize the systemic and renal acid-base response to chronic administration of hypercalcemia-producing agents of diverse chemical nature and mechanism of calcemic action. In thyroparathyroidectomized (TPTX) dogs (group 1, N = 6), chronic oral administration of 1,25-dihydroxycholecalciferol (1,25-(OH)₂D₃; calcitriol) resulted in sustained hypercalcemia and chloride-resistant metabolic alkalosis. Urinary net acid excretion (NAE) remained unchanged. Therefore, the increase in steady-state plasma bicarbonate concentration was independent of the endogenous change in the parathyroid hormone (PTH) and was in part of extrarenal origin because NAE did not increase and in part of renal origin because NAE did not decrease. In response to 1,25-(OH)₂D₃ metabolic alkalosis also occurred in dogs ingesting a low Pi diet (group 2, N = 5) and in dogs that received Pi supplements (group 4, N = 6), but in the former group there was a hypophosphaturic limitation on titratable acid excretion and a decrease in NAE, whereas in the latter group, there was a hyperphosphaturic accentuation of titratable acid excretion and an increase in NAE. Significant increases in plasma bicarbonate concentration and decreases in hydrogen ion concentration also occurred in intact dogs administered large doses of PTH by intermittent injection for 7 days (group 5, N = 6). In this group, as in the TPTX dogs of group 1 administered 1,25-(OH)₂D₃, the changes in systemic acid-base composition occurred in the absence of either increases or decreases in NAE. Thus, chronic PTH administration as well as 1,25-(OH)₂D₃ administration (group 1) resulted in metabolic alkalosis attributable to both extrarenal and renal mechanisms. Maintenance of the metabolic alkalosis, however generated, is inferred to be predominantly dependent on the renal effects of 1,25-(OH)₂D₃ and PTH because without administration of these agents chronic extrarenal alkali input to both normal and TPTX dogs did not result in metabolic alkalosis. In TPTX dogs with chronic hypercalcemia induced by administration of increasing amounts of calcium in substitution for sodium in a continuous intravenous infusion (group 8, N = 3), the plasma bicarbonate concentration decreased and the hydrogen ion concentration increased significantly in association with an increase in NAE. Thus, metabolic acidosis of extrarenal origin occurred and persisted with a directionally appropriate renal homeostatic response. Taken together, the results of the present studies thus suggest that the movement of calcium to or from extracellular fluid (ECF) and bone (and/or soft tissue) in response to hypercalcemia-producing agents is accompanied by a directionally similar movement of base equivalents which results in either metabolic acidosis or alkalosis depending on the direction of net movement of calcium: (1) Calcium infusion → base deposition in bone/soft tissue → metabolic acidosis; (2) 1,25-(OH)₂D₃ or PTH administration → base release from bone → metabolic alkalosis. Moreover, chronic 1,25-(OH)₂D₃ or PTH administration increases the set point at which the plasma bicarbonate concentration is regulated by the kidney and thereby causes metabolic alkalosis to persist.