It is known that estrogen can mitigate menopause-associated urine phosphate retention. A recent cross-sectional study of ambulatory individuals with prevalent cardiovascular disease published in this issue of AJKD explores the role of sex and use of estrogen in phosphate and FGF-23 levels. The author, Dr. Joachim H. Ix (JI) from University of California San Diego, spoke with Dr. Matthew Sparks (eAJKD), web advisory board member, regarding this study.

eAJKD: The data set used in this recently published study comes from the “Heart and Soul Study”. Can you describe what the “Heart and Soul Study”?

JI: This study was designed to look at psychosocial factors and their relationship to cardiovascular disease. The principal investigator was interested in understanding how depression and related disorders influenced cardiovascular disease. The study enrolled about 1000 individuals with known cardiovascular disease and relatively normal kidney function between 2000 and 2002, and collected serum samples and 24-hour urine specimens. The availability of 24-hour urines in a relatively large cohort has been a very valuable source of data for evaluating many things related to kidney function.

eAJKD: What was the major impetus for beginning your study looking at sex, estrogen, and FGF-23 and phosphate levels?

JI: The relationship of high phosphorus levels with vascular calcium deposition and future cardiovascular events in patients with CKD is now well established. What has been exciting to me is that in the last 5 years this relationship has been further extended from patients with CKD to individuals in the general population with normal kidney function. However, factors leading to high phosphorus in the general population are largely unknown.  We have consistently observed that women tend to have higher phosphorus levels than men in the general population, but not until after menopause.

This led us to believe that there might be some protective effect of estrogen on phosphate levels and beyond.

eAJKD: What mechanisms could account for the protective effect of estrogen on phosphate levels?

JI: Studies using a rat model of CKD have shown that estrogen decreases the NaPi2a cotransporter mRNA and protein levels in the renal proximal tubule. Thus, after menopause when estrogen levels decline, there would be higher NaPi2a transporter levels which could explain the decrease in urinary phosphate excretion and higher serum phosphorus levels. However, it is not clear whether estrogen directly influences urinary phosphorus loss. There are two estrogen receptors in renal proximal tubule cells (ER-alpha and ER-beta). A rat study blocked ER-alpha, but did not ablate the effects of estrogen on urinary phosphorus loss. So, estrogen could potentially interact with ER-beta directly in the kidney, or could influence phosphate excretion through other phosphatonins. This led us to investigate the relationship of sex and the phosphatonin FGF-23, since FGF-23 is now recognized as a key regulator of phosphorus homeostasis.

eAJKD: During your study, were you surprised by anything you learned?

JI: The finding that women not on estrogen therapy had higher FGF-23 levels was unknown at the start of our study. This is surprising because there is a study in a rat model of CKD that suggests that estrogen actually increases FGF-23 production in bone. So, if an older woman not on estrogen therapy has declining estrogen levels, one might expect to see lower FGF-23 levels rather than the higher levels observed in our study. If one were to propose an indirect mechanism by which menopause might lead to phosphate retention through FGF23, one might expect the following scenario: As a woman transitions through menopause she becomes relatively estrogen deficient. Since estrogen stimulates FGF23 production in bone, the declining estrogen levels would lead to decreased FGF-23 and phosphate retention. Our data suggests the opposite. Since post-menopausal women had high FGF23 levels, it seems less likely that low post-menopausal FGF-23 is the dominant cause for high phosphorus levels. Conversely, because prior studies show that phosphate loading leads to high FGF-23 levels, our observations suggest that high FGF23 levels might be increasing in response to high phosphate levels.

eAJKD: How do these findings impact patients?

JI: If high FGF23 induces vascular disease, then higher levels after menopause may partially explain why rates of cardiovascular disease in post-menopausal women begin to approach rates in similarly aged men. With FGF-23, we are dealing with a hormone that induces phosphorus loss and calcitriol deficiency. These could potentially influence post-menopausal bone loss and represent a new mechanism responsible for fractures. These will be important topics for future research as we learn more about phosphorus metabolism in the general population. It will be important to develop prospective studies evaluating these parameters in women over time as they transition through menopause into older age, as our current study was designed as a cross-sectional study with measurements at one point in time.

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