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Abstract: TH-PO531

Evidence of Circadian Rhythm of Plasma Activin A, Its Disturbance by CKD, and Contribution of Activin A Secreted from Injured Kidney

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Nordholm, Anders, Herlev Hospital, Copenhagen, Denmark
  • Egstrand, Søren, Herlev Hospital, Copenhagen, Denmark
  • Mace, Maria Lerche, Herlev Hospital, Copenhagen, Denmark
  • Morevati, Marya, Rigshospitalet, Copenhagen, Denmark
  • Olgaard, Klaus, Rigshospitalet, Copenhagen, Denmark
  • Lewin, Ewa, Herlev Hospital, Copenhagen, Denmark
Background

Activin A is an interesting new factor in CKD-MBD. It is a member of the TGF-β family, essential in kidney development and repair. Increased systemic activin A might be a biomarker of CKD-MBD that can be targeted for CKD-MBD prevention and therapy. Disrupted circadian rhythm (CR) causes detrimental health effects and CRs are observed in mineral metabolism. Our hypothesis is that increase in circulating levels of activin A is associated with disruption of circadian rhythm of plasma activin A, and parameters of mineral homeostasis in CKD.

Methods

CRs of activin A (pg/ml), FGF23 (pg/ml), PTH (pg/ml) and P (mM) were measured every 6th hour in control (Ctr) and CKD rats (5/6 nephrectomy) on low (LP), standard (SP), and high phosphate (HP) diet (N=8-26). Isolated renal vein and artery sampling was performed in kidney injury rats (14 days unilateral ureter obstruction, UUO) and healthy Ctr.

Results

Activin A was 2.5-fold higher in renal vein compared to artery in UUO (V:246±22, A:100%, p<0.05) but unaltered in Ctr (V:100±6, A:100%, ns) indicating renal secretion in kidney injury.
Plasma activin A exhibited CR in Ctr (p<0.01 by cosinor analysis) with 300% higher values at acrophase (437±59) compared to nadir (106±7) (p<0.05). CKD obliterated the CR of activin A. Plasma FGF23 showed CR in Ctr (p<0.05) with peak at 14:00 (877±42), while the CR was obliterated in CKD rats on LP and SP even though FGF23 was suppressed in CKD LP (p<0.05). In CKD HP FGF23 was increased (p<0.01) and the CR was disturbed with shift in acrophase to 09:00 (4173±316). Plasma PTH exhibited CR in Ctr (p<0.0001), while the rhythm was disturbed in CKD (p<0.05) despite prevention of sHPT in CKD LP (p<0.05). Plasma P showed CR in all groups (p<0.05). However, the CR was disturbed in all CKD groups with shift in acrophase from 16:00 in Ctr to 19:00 (LP), 17:00 (SP), and 00:00 (HP).

Conclusion

Existence of a circadian rhythm of circulating activin A is established for the first time. The rhythmicity of activin A is disturbed in CKD rats and is associated with disturbed circadian rhythms of P and P regulating hormones PTH and FGF23. In injured kidney activin A is induced and secreted to venous effluent which can contribute to the disturbed circadian rhythm of activin A in uremia.