Whole or Fragmentary Information on Parathyroid Hormone?

Abstract

M ore than a decade ago, Brossard et al. (1) drew attention to the fact that the so-called "intact," second-generation parathyroid hormone (PTH) assays measured not only the PTH-(1-84) molecule but also large PTH fragments in patients with chronic kidney disease (CKD). One of the major problems is that the proportion of PTH-(1-84) and its fragments in the circulation changes in response to the serum level of ionized calcium; therefore, in presence of hypercalcemia, the parathyroid gland releases less PTH-(1-84) but more PTH fragments. The reverse is true in the presence of hypocalcemia, where more active PTH-(1-84) is needed. The difference is particularly striking in patients with CKD. When considering the potential biologic relevance of this finding, it is even more disturbing that at least one of the fragments, namely PTH-(7-84), has been shown to act as a partial antagonist of PTH-(1-84), with opposite biologic activities (2-4). Progressive awareness of these methodologic problems and the underlying biologic complexity went along with the development of thirdgeneration PTH assays that recognize only PTH-(1-84), also called "whole," "bio-intact," or "biologically active" PTH (5).Theoretically, the assessment of second-and third-generation PTH assays combined should reflect parathyroid activity more adequately than second-generation assays alone, reflecting the sum of potentially opposing effects of PTH-(1-84) and its fragments. Several authors explored changes of serum PTH levels, as measured with various assays, with progression of CKD and in response to medical interventions. Reduction in GFR is accompanied by a higher increase in large PTH-related C-terminal fragments than in PTH-(1-84) in patients with CKD (6,7). The administration of cinacalcet to patients with stage 5 CKD and secondary hyperparathyroidism (8) or to patients with parathyroid cancer (9) did not change the ratio between intact PTH (iPTH) and PTH-(1-84). This is somewhat surprising because cinacalcet reduces serum calcium, and hypocalcemia is associated with changes in the PTH ratio. In contrast, surgical parathyroidectomy, which often leads to profound hypocalcemia, has been shown to normalize the ratio (10).In an original article in this issue, Monier-Faugere et al. (11) report the effects of the administration to long-term hemodialysis patients of calcitriol, the most active metabolite of vitamin D, and its active derivative paricalcitol on circulating levels of PTH-(1-84), iPTH, large C-terminal PTH fragments (C-PTH), and the PTH-(1-84)/C-PTH fragment ratio, also called PTH-(1-84)/C-PTH-(7-84) ratio. They present results that were obtained first in a longitudinal, crossover design study that compared paricalcitol with calcitriol and second in a cross-sectional study that compared paricalcitol with no vitamin D treatment. In the longitudinal study, they observe a lower PTH ratio in response to calcitriol but a higher PTH ratio in response to paricalcitol, as compared with respective baseline values. In the cross-sectional study, they fi...

Kidney bone disease and mortality in CKD: revisiting the role of vitamin D, calcimimetics, alkaline phosphatase, and minerals

“…The PTH-(7-84), has been shown to act as a partial antagonist of PTH-(1-84), with opposite biologic activities. 34, 35 In CKD patients reduction in renal function is accompanied by a higher increase in C-PTH than in PTH-(1-84). 36 The administration of cinacalcet to dialysis patients with SHPT 37 or to patients with parathyroid cancer 38 does not change the ratio between intact PTH and PTH-(1-84).…”

“…36 The administration of cinacalcet to dialysis patients with SHPT 37 or to patients with parathyroid cancer 38 does not change the ratio between intact PTH and PTH-(1-84). 34 Among VDRAs, paricalcitol has less hypercalcemic and hyperphosphatemic effects and does not induce low bone turnover in a rat model of renal failure. 39 Also, the affinity of paricalcitol for vitamin D receptor is three times less than that of calcitriol , whereas its calcemic and phosphatemic effects have been shown to be 10 times lower.…”