HDCN Article Review/Hyperlink

Ouseph R, Leiser JD, Moe SM

Calcitriol and the parathyroid hormone -- ionized calcium curve: a comparison of methodologic approaches

J Am Soc Nephrol (Mar) 7:497-505 1996

Objective: To clarify the effect of calcitriol on the inverse sigmoidal relationship between parathyroid hormone (PTH) and ionized calcium (iCa).

Methods: PTH-iCa curves were constructed in 8 chronic hemodialysis patients with mild to moderate secondary hyperparathyroidism (PTH 289-839 pg/mL, nl < 65) by inducing hypo- and hypercalcemia through alterations in dialysate calcium concentrations. Studies were performed during treatment with low-bicarbonate (25 mM) and standard-bicarbonate (35-40 mM) dialysate in order to determine the effect of acute metabolic acidosis on the PTH-iCa curve. Subsequently, patients were treated with 0.02 ug/kg calcitriol intravenously after each HD session for 4 weeks and the PTH-iCa curves repeated. The inverse sigmoidal relationship between PTH and iCa was analyzed using a full curve four-parameter fit (max PTH, min PTH, set point and slope) as well as a graphical fit. The slope of the curve was expressed as a non-normalized slope as well as a normalized slope (i.e., non-normalized slope divided by (maxPTH - minPTH)) to correct for different magnitudes of PTH response. Use of the normalized slope thus partially corrects for gland mass and cell-secretory capacity, thereby allowing determination of the sensitivity of secretory activity to changes in iCa level.

Results: Calcitriol decreased basal, maximal and minimal PTH and non-normalized slope, but did not affect set point or normalized slope. Acute metabolic acidosis did not affect the PTH-iCa relationship.

Conclusion: Caclitriol appears to decrease parathyroid gland functional mass (i.e., decreases PTH levels) but does not affect the sensitivity of the gland to changes in iCa concentration.

Comment: This is a rigorously performed study that clarifies the realtionship between PTH and iCa in secondary hyperparathyrodism. Increased PTH in uremia may be due to several mechanisms, including 1) increased tissue mass, resulting in increased secretion of hormone; 2) increased tissue mass plus altered calcium set-point, i.e., the iCa concentration required to inhibit 50% of maximal PTH secretion, necessitating higher iCa levels to inhibit PTH secretion; 3) increased tissue mass, set-point, plus a change in the slope of the sigmoid curve, possibly indicating heterogeneity of set-points among parathyroid cells (this is the most often cited mechanism). The data of Ouseph et al. do not support an alteration in set-point; rather, these authors conclude that calcitriol appears to lower PTH levels by decreasing functioning tissue mass. Their data are consistent with the observation that the iCa level that maximally suppresses PTH secretion (10.4-11.2 mg/dl total calcium) is unchanged in ESRD patients with secondary hyperparathyroidism. (David J. Leehey, M.D., Loyola University School of Medicine)