SO069CIRCADIAN RHYTHMS OF THE BONE-MINERAL AXIS IN HEMODIALYSIS PATIENTS
Authors: Jiao Yue , Chen Chen , Larkin John , Winter Anke , Usvyat Len A , Stauss-Grabo Manuela , Hymes Jeffrey , Maddux Franklin 
Published: June 2020

Abstract

Background and Aims
Chronic kidney diseases disrupt normal bone-mineral axis endocrine functions causing the onset of mineral bone disorders (MBDs). The general and hemodialysis (HD) populations have been found to exhibit diurnal rhythms in phosphate (PO4), calcium (Ca), and parathyroid hormone (PTH) regulation (Trivedi et al. J Nephrol. 2015), but reference values for fluctuations have not been established in HD patients and do not consider PO4 binder use. We profiled the diurnal rhythms of MBD labs overall and stratified by PO4 binder use in a large nationally representative HD population in the United States.

Method
We used prevalent in-center HD patient (vintage &gt;90 days) data on adults (age ≥18 years) treated at a dialysis organization in 2018. Mean annual pre-HD blood PO4, corrected Ca, and intact PTH levels were computed in 2-hour periods through 24 hours for the population and stratified by binder use. HD initiation time was a varying exposure, allowing patients to switch time groups if blood draws occurred in multiple time periods. Mean MBD lab levels with 95% confidence limits were plotted using nonparametric smoothing spline models to fit data and calculate trajectories throughout the day.

Results
The population of adult HD patients (n=156,873) was: mean age 62.8±14.3 years, 57.1% male, 58.2% white race, 41.9% with diabetes, 19.6% with congestive heart failure, and HD vintage 1510±1289 days. Mean pre-dialysis albumin=3.8±0.4 g/dL, PO4=5.4±1.5 mg/dL, corrected Ca=9.1±0.6 mg/dL, PTH=468±333 pg/dL for the population. Mean PO4, corrected Ca and PTH levels varied remarkably by 0.9 mg/dL, 0.2 mg/dL, and 186 pg/dL throughout the day. For PO4 and PTH, nadir levels occurred from 0900 to 1100 hours (5.3±1.6 mg/dL and 473±340 pg/dL), followed by a rise to a mid-day peak from 1700 to 1900 hours (5.8±1.8 mg/dL and 562±401 pg/dL), and the highest levels had a peak time from 2300 to 0100 hours (6.2±2.1 mg/dL and 659±389 pg/dL) (Figure 1A & C). Corrected Ca showed relatively inverse fluctuations to PO4
and PTH, with peak levels from 1100 to 1300 hours (9.2±0.7 mg/dL) and nadir levels from 1900 to 2100 hours (9.0±0.7 mg/dL) (Figure 1B). Similar fluctuations and levels were observed for PO4 and PTH among patients using any phosphate binder type (90.7%), however, patients not using a phosphate binder exhibited absolute values that were persistently lower at every timepoint (Figure 1D & F). Corrected Ca levels were similar by any binder use (Figure 1E).

Conclusion
Our results suggest PO4, Ca, and PTH levels have a diurnal variation of 0.9 mg/dL, 0.2 mg/dL, and 186 pg/dL in hemodialysis patients. PO4 and PTH exhibit a nadir in the morning, a mid-day peak and a larger nocturnal peak. Ca exhibits relatively inverse diurnal fluctuations with PO4 and PTH. Patients using any binder exhibit similar fluctuations and levels of PO4 and PTH; while patients not requiring a binder have similar fluctuations, yet persistently lower levels of PO4 and PTH. Given PO4 binder and calcimimetic therapies are commonly used for treatment of MBDs based on pre-dialysis blood levels, these findings provide insights for further research and pose the question if algorithms are warranted to compute daily time-adjusted levels for MBD laboratories.