Intact parathyroid hormone and whole parathyroid hormone assay results disagree in hemodialysis patients under cinacalcet hydrochloride therapy

Abstract

Background: The parathyroid gland secretes 1-84 and 7-84 parathyroid hormone (PTH) fragments, and its regulation is dependent on stimulation of the extracellular calcium-sensing receptor. While the intact PTH system detects both PTH fragments, the whole PTH system detects the 1-84PTH but not the 7-84PTH. Cinacalcet hydrochloride (CH) binds to calcium-sensing receptor as a calcimimetic. Here we investigated the role of CH treatment in the assessment of parathyroid gland function.

Methods: Stable adult dialysis patients for whom CH therapy was planned were included. Patients for whom CH therapy was not planned were simultaneously included as the control group.

Results: The CH group (n = 44) showed significantly higher circulating levels of Ca, intact PTH, and whole PTH, before the CH treatment than the control group (n = 112). The Ca, intact PTH, and whole PTH levels decreased along with the CH therapy, and the Ca levels became comparable in the 8th week of treatment and thereafter. The CH group in the 8th week and thereafter showed significantly lower whole/intact PTH ratios than the control group, while the whole/intact PTH ratio was not significantly different between before and during the CH therapy. A multiple regression analysis revealed that the whole/intact PTH ratio was almost constant, but both the serum Ca level and a CH therapy could potentially modify the fixed number. When the whole PTH levels were estimated by intact PTH levels using the relationship between them in the control group, the levels were clearly overestimated in the CH group.

Conclusions: Although the direct effect of CH on the whole/intact PTH ratio is masked by its hypocalcemic action, we could successfully demonstrate that the ratio in CH users is lower than that in the non-users with comparable levels of serum Ca. Evaluating parathyroid function with intact PTH according to the clinical practice guidelines in patients being treated with CH may lead to significant overestimation and subsequent overtreatment.

Fig. 1

Generally, the serum Ca concentration decreased along with the time course of CH therapy. Since the serum Ca level is another important determinant of the whole/intact PTH ratio, the pure effect of CH on the whole/intact PTH ratio cannot be evaluated by comparing the data obtained from the same patients between before (A) and during/after (B) CH therapy. Therefore, we established a control group of patients (C) whose parathyroid functions were stable even without using CH in this protocol. When the serum Ca levels became comparable between B and C, then the only difference in the major determinant of the whole/intact PTH ratio was the use of CH, and thus we could evaluate the pure effect of CH

Fig. 2

Analyzing principle used to assess the effect of the whole/intact PTH change in clinical practice. The JSDT guidelines set two standard PTH levels: intact PTH levels between 60 and 240 pg/mL and whole PTH levels between 35 and 150 pg/mL. If the relationship between these two assay results is always constant, the diagnoses made by these two standard levels would agree, and therefore the patients would be classified into successful diagnosis (S) in the majority of cases. However, if CH therapy modifies the relationship between these assay results, the numbers of cases classified into under-diagnosis (U) or over-diagnosis (O) may be increased, which becomes a potential cause of false diagnosis at bedside

Fig. 3

The changes in biochemical data during CH therapy. The serum levels of Ca, Pi, intact PTH, and whole PTH decreased along with the CH therapy. Although the CH group showed higher serum Ca levels before the initiation of the CH therapy, the levels became comparable with the control group at the 8th week and thereafter. C the control group, CH the cinacalcet hydrochloride group. *p < .05, ***p < .001 versus C

Fig. 4

The relationship between intact PTH and whole PTH in the control and CH groups at weeks 8, 12, 16, 24, and 48. These values all showed tight correlations; however, the regression lines were steeper in the CH groups. *p < .05 versus the steepness in the control group

Fig. 5

The comparison of the whole/intact PTH ratios. The CH at 8, 12, 16, 24, and 48 weeks showed significantly lower whole/intact PTH ratios than the control group. Although the serum Ca levels were different between the control and the CH groups at 0 W, the difference in the whole/intact PTH ratios did not reach significant level. The serum Ca levels were comparable between the control and CH groups at the 8th week and thereafter. Therefore, the difference in the whole/intact PTH ratios between these groups would be attributable solely to the CH therapy. On the other hand, the whole/intact PTH ratios were not significantly different between those before and during the CH therapy. **p < .01, ***p < .001 versus C