Abstract
Background and Aims
There are disparities in the diagnosis, treatment and prognosis for cardiovascular disease (CVD) between sexes and these differences are rooted, in part, in biology. Abnormalities in phosphate regulation and vascular calcification are important risk factors for CVD, even in the setting of preserved kidney function. Elevations of serum phosphate within the normal range are a risk factor for CVD. Abnormalities and differences in phosphate regulation are often not reflected in single circulating measurements of serum phosphate, but can be revealed by the acute circulating and mineral response to an oral phosphate challenge. The aim of this study was to assess the differences between sexes in the hormonal response and excretion capacity of an oral phosphate challenge.
Method
Healthy people (N=78) free of type 2 diabetes (T2D) and symptomatic CVD (∼10 males and ∼10 females from each decade between 40 and 80 years) were recruited from Kingston, Ontario, Canada. Following a 12-hour fast, participants consumed a 1250 mg phosphate drink (sodium phosphate) where blood and urine were collected hourly from baseline to 4 hours following the oral challenge.
Results
In the cohort, 43 of the participants were female and the average age for males and females was 58.4±10.8 and 60.0±9.6, respectively. Kidney function was normal, with eGFR measurements of 88±12ml/min/1.73m2 and 93±14ml/min/1.73m2, in males and females respectively. There was no difference in fasting baseline levels of phosphaturic hormones, fibroblast growth factor 23 (FGF-23) or parathyroid hormone (PTH) between sexes, nor was there an impact of age on either of these measures. Females had a similar fasted urinary phosphate-to-creatinine ratio as males, but higher circulating serum phosphate (1.2±0.1 mM v 1.0±0.1 mM, p<0.01). In response to the phosphate challenge, females increased their phosphate excretion more than males, significant for all measured time points (Figure 1A). There was a substantial increase in urinary excretion of calcium in females only (Figure 1B). Circulating calcium was not altered by the challenge nor different between the sexes. After adjustment for sex and age, testosterone was inversely correlated with fasted serum phosphate (r=-0.20) and urinary phosphate-to-creatinine ratio (r=-0.28), but not to measures of acute response to the oral challenge. Estradiol was not correlated to any measure of phosphate homeostasis, but correlated negatively to serum calcium (r=-0.30) and positively with post-challenge urinary calcium excretion (r=0.22), after adjustment for age and sex.
Conclusion
Females have greater capacity to excrete a phosphate load than males and also excrete calcium in response to phosphate. Impaired acute phosphate response may lead to increased exposure to circulating phosphate, and in that way may contribute to the initiation or propagation of vascular calcification. Improved acute handling of phosphate may contribute to the lower prevalence of coronary artery calcification and lower risk of developing CVD in females. Phosphate as a stimulus for acute calcium excretion, as well as its correlation to estradiol, has potential importance in relation to dietary phosphate exposure and osteoporosis. These observed differences in mineral homeostasis between females and males may be important as, to date, there has been no attempt to identify sex-specific targets or sex-specific treatment approaches.
Phosphate and Cardiovascular Disease beyond Chronic Kidney Disease and Vascular Calcification
