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Kidney Week

Abstract: TH-PO142

Chronotherapy With Cinacalcet Has a Striking Effect on Inhibition of Parathyroid Gland Proliferation in Rats With Secondary Hyperparathyroidism

Session Information

  • CKD-MBD: Targets and Outcomes
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Egstrand, Søren, Dept. of Nephrology, Herlev Hospital, Copenhagen, Denmark
  • Mace, Maria Lerche, Dept. of Nephrology, Rigshospitalet, Copenhagen, Denmark
  • Morevati, Marya, Dept. of Nephrology, Rigshospitalet, Copenhagen, Denmark
  • Olgaard, Klaus, Dept. of Nephrology, Rigshospitalet, Copenhagen, Denmark
  • Lewin, Ewa, Dept. of Nephrology, Herlev Hospital, Copenhagen, Denmark
Background

Secondary hyperparathyroidism (sHPT) is associated with parathyroid hyperplasia, bone and vascular disease. Cinacalcet is a modulator of the calcium-sensing receptor used to treat sHPT. Aim was to examine whether taking the circadian rhythm into account might improve treatment response.

Methods

CKD was induced by 5/6-nephrectomy in 40 rats. After 4 weeks, 20 CKD rats had Cinacalcet 2.5mg/d by oral gavage either morning (early inactive phase: Cina1, N=10) or evening (early active phase: Cina2, N=10). After 3 weeks, parathyroid glands, aorta and femur were harvested from Cinacalcet treated rats either morning or evening, 24 h since treatment, and compared to untreated CKD rats (PNX1 and PNX2) and healthy rats. Parathyroid proliferation was assessed by Ki-67 immunostaining, aortic calcium content by the o-cresolphthalein method and bone by µCT.

Results

Ki-67 index was significantly decreased in Cina1 (0.92±0.14%) compared to Cina2 (2.46±0.37%, p=0.006) and to the two untreated CKD groups (3.45±0.47% and 4.14±0.47%, p=0.0002 and p=0.0001). In healthy control groups: 1.53±0.17% and 1.45±0.19% (Fig.1). Plasma PTH was decreased by 55% in Cina1 compared to PNX1 (2279±447pg/ml vs 5076±1740pg/ml) and by 29% in Cina2 compared to PNX2 (2667±594pg/ml vs 3756±911pg/ml). Aortic calcium content and bone porosity were similarly increased in all CKD groups.

Conclusion

Administration of Cinacalcet early in the inactive period markedly decreased the proliferation of the parathyroid glands in sHPT compared to dosing early in the active period indicating an advantage of chronotherapy in a translational model of sHPT.

ctrl1: Healthy rats (morning)
ctrl2: Healthy rats (evening)
cina1: Cinacalcet treated CKD rats (morning)
cina2: Cinacalcet treated CKD rats (evening)
PNX1: Untreated CKD rats (morning)
PNX2: Untreated CKD rats (evening)