Associations of time-dependent changes in phosphorus levels with cardiovascular diseases in patients undergoing hemodialysis: results from the Japan Dialysis Active Vitamin D (J-DAVID) randomized clinical trial

Eri Koshi-Ito; Daijo Inaguma; Haruka Ishii; Yukio Yuzawa; Daijiro Kabata; Ayumi Shintani; Masaaki Inaba; Masanori Emoto; Katsuhito Mori; Tomoaki Morioka; Shinya Nakatani; Tetsuo Shoji

doi:10.1093/ckj/sfac172

Associations of time-dependent changes in phosphorus levels with cardiovascular diseases in patients undergoing hemodialysis: results from the Japan Dialysis Active Vitamin D (J-DAVID) randomized clinical trial

Clin Kidney J. 2022 Aug 3;15(12):2281-2291. doi: 10.1093/ckj/sfac172. eCollection 2022 Dec.

Authors

Eri Koshi-Ito^{1

2}, Daijo Inaguma^{1

3

4}, Haruka Ishii⁵, Yukio Yuzawa¹, Daijiro Kabata⁵, Ayumi Shintani⁵, Masaaki Inaba^{3

6

7

8}, Masanori Emoto^{3

6

7

8}, Katsuhito Mori⁸, Tomoaki Morioka⁷, Shinya Nakatani⁷, Tetsuo Shoji^{3

9

6}

Affiliations

¹ Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
² Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine.
³ J-DAVID Investigators.
⁴ Department of Internal Medicine, Fujita Health University Bantane Hospital, Aichi, Japan.
⁵ Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan.
⁶ Vascular Science Centre for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan.
⁷ Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
⁸ Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan.
⁹ Department of Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.

Abstract

Background: While the risk of exceeding the standard range of phosphorus levels has been investigated, the impact of the degree of fluctuations has not been investigated.

Methods: Data were derived from the Japan Dialysis Active Vitamin D trial, a 4-year prospective, randomized study involving 976 patients without secondary hyperparathyroidism undergoing hemodialysis in Japan. Laboratory data were collected every 6 months and the primary outcome was the time to the occurrence of cardiovascular events. The effect of time-dependent changes in phosphorus levels was assessed using a time-varying Cox proportional hazards regression model.

Results: The median serum phosphorus levels at baseline and at the final observation were 4.70 mg/dl [interquartile range (IQR) 3.90-5.30] and 5.00 mg/dl (IQR 4.20-5.80), respectively. Over each 6-month period, phosphorus changes ranged from -7.1 to +6.7 mg/dl, with a median value of -0.1 to +0.3 mg/dl. During follow-up, composite cardiovascular events occurred in 103 of 964 patients. Although the P-value for the interaction between serum phosphorus level fluctuations and baseline phosphorus levels was insignificant, the following trends were observed. First, patients with relatively high initial phosphorus levels over a 6-month period showed a trend towards a higher hazard, with greater changes in the phosphorus level over the 6-month period. Second, it was suggested that oral vitamin D receptor activators could contribute to the relationship between fluctuating phosphorus levels and cardiovascular events.

Conclusions: Our results suggest the importance of maintaining stable phosphorus levels, not only in the normal range, but also without fluctuations, in the risk of cardiovascular events among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis.

Keywords: CKD-MBD; cardiovascular disease; chronic renal insufficiency; fluctuation; hemodialysis; phosphorus; vitamin D receptor activator.