Abnormal Regulation of Parathyroid Hormone Release by Calcium in Secondary Hyperparathyroidism due to Chronic Renal Failure*

Abstract

Dispersed parathyroid cells were employed to study calcium-regulated parathyroid hormone (PTH) release in severe secondary hyperparathyroidism due to chronic renal insufficiency. Cell preparations were obtained from 16 parathyroid glands of 6 patients undergoing subtotal parathyroidectomy for parathyroid bone disease and/or hypercalcemia. The effects of increasing ambient calcium concentration on immunoreactive PTH release in vitro were assessed and compared with results observed in cells prepared from 7 adenomas and 6 normal parathyroid glands. There was no difference in maximal PTH release for the 3 types of tissue (mean +/- SEM, 8.48 +/- 1.9 , 8.1 +/- 3, and 10.1 +/- 0.78 ng/10(5) cells. h respectively). In 14 of 16 hyperplastic glands, 6 of 7 adenomas, and all of the normal glands, PTH release was inhibited more than 50% by 2-3 mM calcium (suppressible glands). Of the normal glands, half of the maximal inhibition of PTH release (the set-point) occurred at less than 1.03 mM calcium in 5 of 6 cases. In 12 of 14 suppressible hyperplastic glands and all of the 6 suppressible adenomas, on the other hand, the set-point was 1.03 mM or higher (p less than 0.01 and P less than 0.002, respectively). Thus, in severe secondary parathyroid hyperplasia due to chronic renal insufficiency, there is frequently an increase in the set-point for calcium without a change in the maximal secretory rate per cell. Abnormal calcium-regulated PTH release at the cellular level, therefore, is not limited to parathyroid neoplasia (i.e. adenoma or primary hyperplasia), but may occur in secondary hyperplasia as well.

The influence of the progression of secondary hyperparathyroidism on the set point of the parathyroid hormone-calcium curve

“…Thus, the correlation between Cab and the set point decreased at 5-6 weeks of 2 HPT. The increase in the set point found at 5-6 weeks, when compared with 2-3 weeks, is in agreement with previous reports that have identified a tendency to an increased set point of the PTH-Ca 2+ curve in the course of primary (Brown et al 1979) and secondary (Brown et al 1982, Malberti et al 1993, Goodman et al 1998 hyperparathyroidism. However, in these studies the progression of hyperparathyroidism was accompanied by an increase in extracellular Ca 2+ while in our study plasma Ca 2+ remained low.…”

“…In vitro experiments using parathyroid glands excised from azotemic patients with severe 2 HPT have shown an increase in the set point, which may represent an intrinsic abnormality of PTH secretion (Brown et al 1982). However, clinical studies with hemodialysis patients have provided a variety of results.…”

Association of vitamin D receptor gene polymorphisms with end-stage renal disease and the development of high-turnover renal osteodystrophy in a Chinese population

“…However, the results remain controversial among the reported studies, and the effect of these SNPs in the VDR gene on ESRD risk in the Chinese population remains unclear (Fernández et al, 1997;Wang et al, 2004;El-Shehaby et al, 2013). Furthermore, vitamin D and its receptor have important roles in determining calcium-regulated parathyroid hormone (PTH) secretion (Brown et al, 1982). Few studies have reported the association of genetic variants of the VDR gene with the development of renal osteodystrophy (RO) in patients with ESRD.…”

Persistent Downregulation of Calcium-Sensing Receptor mRNA in Rat Parathyroids when Severe Secondary Hyperparathyroidism Is Reversed by an Isogenic Kidney Transplantation

“…It presumably involves dysfunction of the mechanism by which the parathyroid cells sense changes in plasma calcium (4). PG from patients with severe secondary or tertiary hyperparathyroidism (HPT) have an elevated set-point for Ca ϩϩ in vitro (5). A substantial reduction in the expression of the Ca ϩϩ -sensing receptor (CaR) protein and mRNA has been demonstrated in hyperplastic parathyroid glands from uremic patients (6,7).…”