Development of experimental chronic kidney disease and vascular calcification alters diurnal variation of phosphate and its hormonal regulators

Abstract

The mineral‐bone axis is tightly regulated and dependent on renal function. In chronic kidney disease (CKD) progressive loss of renal capacity disrupts this axis over‐time, with marked changes in circulating calcium, phosphate, PTH, and fibroblast growth factor‐23 (FGF‐23). These changes contribute to the development of cardiovascular disease, like vascular calcification (VC), which worsens morbidity and mortality in CKD. Although the chronic changes in these circulating factors and their relationships are well known, no experimental studies have examined how the progressive development of CKD and VC alter the circadian rhythms of these factors. An adenine‐induced experimental model of CKD in rats was used to establish (i) general circulating trends, (ii) if renal dysfunction affects these observed trends, and (iii) identify potential changes in these trends caused by VC. This study clearly discerned patterns of daily variations in circulating minerals and hormones, finding that both phosphate and PTH follow modelable diurnal variations whereas calcium and FGF‐23 maintain relative stability over 24‐hr. Surprisingly, the development of CKD was not sufficient to disrupt these patterns of diurnal variation and only altered the magnitude of change; however, it was found that the diurnal rhythms of circulating phosphate and daily stability of calcium were only significantly altered in the setting of CKD with established VC.

Adjusting phosphate feeding regimen according to daily rhythm increases eggshell quality via enhancing medullary bone remodeling in laying hens

“…What need to be studied is whether the MB remodeling and eggshell formation efficiency could be improved by strengthening the phosphate circadian rhythms, especially when the serum phosphate lost its rhythms in cases of metabolic diseases, aging and nutritional disorders [17,33,34]. Indeed, abnormal phosphate rhythm has repeatedly been described as a typical symptom in bone and kidney related diseases in humans and animals [19,32]. Not surprisingly, the management of phosphate rhythm is difficult, and, despite multifaceted approaches have been tested regarding nutritional intervention [35,36] and metabolic regulation [37], it remains unsuccessful or at least inefficient.…”

“…Circadian rhythm disturbance of intestinal, renal and skeletal functions could induce abnormal phosphate rhythm and subsequently cause tissue mineralization disorders [16,17]. For example, chronic kidney disease-mineral bone disorder, which exhibits a decreased serum phosphate circadian rhythm (amplitude decreases and phase shift) [18,19], is often accompanied by circadian rhythm disturbances in the bone [20] and kidney [16]. In this case, simply increasing/decreasing dietary phosphate concentrations, could only overall increase/decrease serum phosphate concentrations, but could not normalize the circadian rhythm of serum phosphate [18].…”

Circadian rhythms and renal pathophysiology

“…This raises the intriguing possibility that the circadian system might regulate serum phosphate levels. Although reports of altered rhythmicity of serum phosphate with CKD in human subjects are variable, a recent study of mice with adenine-induced kidney disease suggests that circadian rhythmicity of phosphate is disrupted only by a high-phosphate diet and induction of vascular calcification ( 47 ). However, the molecular mechanisms underlying these observations remain to be elucidated, and whether circadian disruption can lead to vascular calcification needs further study.…”