Response to Letter to the Editor: “Fibroblast Growth Factor 23, Mineral Metabolism, and Adiposity in Normal Kidney Function”

Response to Letter to the Editor: “Fibroblast Growth Factor 23, Mineral Metabolism, and... We thank Dr. Remer for his commentary on our recent publication that demonstrated an independent association between higher body adiposity and higher fibroblast growth factor 23 (FGF23) levels (1). Dr. Remer’s first point suggests that the observation that higher adiposity is associated with higher FGF23 may be obvious: higher adiposity results in higher insulin levels, and the rise in insulin should result in greater renal phosphate reabsorption “and, in turn, higher FGF23 production is required to compensate for rising plasma phosphate.” However, this conclusion fundamentally misses the main findings of our study, which we will underscore here again. We first observed that with higher adiposity (measured via multiple metrics, including body mass index, waist circumference, waist-to-hip ratio, and visceral adiposity measured via computed tomography) was independently associated with higher FGF23 levels. To evaluate potential mechanisms for this association, we included known predictors of FGF23, including phosphate, parathyroid hormone, and vitamin D, in our analysis. Importantly, regardless of the metric used to quantify adiposity, higher adiposity was associated with higher FGF23 levels, lower serum phosphate, and higher urinary phosphate excretion. These findings suggest that there was greater FGF23 secretion with higher adiposity, despite a negative phosphate balance. Thus, in contrast to Dr. Remer’s assertion that we did not consider phosphate metabolism as a potential mechanism, we did indeed, and we observed the opposite of the conventional physiology: higher FGF23 levels were detected with higher adiposity despite the fact that serum phosphate was lower. This unexpected relationship led us to consider that FGF23 physiology and phosphate metabolism with greater adiposity may be unique. We speculated that the main driver here could be excessive secretion of FGF23 in obesity (primary problem) or some other secondary phenomenon that is not currently recognized. Dr. Remer’s second point asserts that with greater adiposity there is “an incipient kidney impairment frequently going along with increased urinary acidity” as well as a consequent increase in FGF23 levels due to the “antiphosphaturic reductions in the demand for buffering excess urinary acid equivalents.” Although we did not have the necessary data to conduct comprehensive analyses on acid-base status, we presented sufficient data to suggest that this mechanism is unlikely to explain the association between higher adiposity and higher FGF23 levels. First, we did not observe antiphosphaturic effects with higher adiposity; rather, as mentioned earlier, with every metric of higher adiposity we used, there was a greater urinary excretion of phosphate. Second, we specifically selected a population with normal kidney function; participants with estimated glomerular filtration rates of <60 mL/min/1.73 m2 were excluded from our analyses, and the mean glomerular filtration rate across quartiles of adiposity was comparable and >80 mL/min/1.73 m2. Thus, the assertion that impaired acid/base balance resulting in decreased phosphaturia could explain the higher FGF23 with higher adiposity in our study is the exact opposite of what we report: higher adiposity was associated with greater FGF23 and higher urinary excretion of phosphate, despite lower serum phosphate and normal kidney function. Ultimately, it must be restated that our study was observational and cross-sectional and not designed to determine the mechanism underlying our main finding. Although we postulated a potentially novel regulation of FGF23 in states of higher adiposity that appears to be independent of its conventional physiologic regulators (such as phosphate balance, vitamin D metabolism, and kidney function), more investigation will be needed to disentangle the mechanisms that contribute to this observation. Abbreviations: FGF23 fibroblast growth factor 23. Reference 1. Zaheer S, de Boer IH, Allison M, Brown JM, Psaty BM, Robinson-Cohen C, Michos ED, Ix JH, Kestenbaum B, Siscovick D, Vaidya A. Fibroblast growth factor 23, mineral metabolism, and adiposity in normal kidney function. J Clin Endocrinol Metab . 2017; 102( 4): 1387– 1395. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Response to Letter to the Editor: “Fibroblast Growth Factor 23, Mineral Metabolism, and Adiposity in Normal Kidney Function”

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Publisher
Endocrine Society
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2017-02251
Publisher site
See Article on Publisher Site

Abstract

We thank Dr. Remer for his commentary on our recent publication that demonstrated an independent association between higher body adiposity and higher fibroblast growth factor 23 (FGF23) levels (1). Dr. Remer’s first point suggests that the observation that higher adiposity is associated with higher FGF23 may be obvious: higher adiposity results in higher insulin levels, and the rise in insulin should result in greater renal phosphate reabsorption “and, in turn, higher FGF23 production is required to compensate for rising plasma phosphate.” However, this conclusion fundamentally misses the main findings of our study, which we will underscore here again. We first observed that with higher adiposity (measured via multiple metrics, including body mass index, waist circumference, waist-to-hip ratio, and visceral adiposity measured via computed tomography) was independently associated with higher FGF23 levels. To evaluate potential mechanisms for this association, we included known predictors of FGF23, including phosphate, parathyroid hormone, and vitamin D, in our analysis. Importantly, regardless of the metric used to quantify adiposity, higher adiposity was associated with higher FGF23 levels, lower serum phosphate, and higher urinary phosphate excretion. These findings suggest that there was greater FGF23 secretion with higher adiposity, despite a negative phosphate balance. Thus, in contrast to Dr. Remer’s assertion that we did not consider phosphate metabolism as a potential mechanism, we did indeed, and we observed the opposite of the conventional physiology: higher FGF23 levels were detected with higher adiposity despite the fact that serum phosphate was lower. This unexpected relationship led us to consider that FGF23 physiology and phosphate metabolism with greater adiposity may be unique. We speculated that the main driver here could be excessive secretion of FGF23 in obesity (primary problem) or some other secondary phenomenon that is not currently recognized. Dr. Remer’s second point asserts that with greater adiposity there is “an incipient kidney impairment frequently going along with increased urinary acidity” as well as a consequent increase in FGF23 levels due to the “antiphosphaturic reductions in the demand for buffering excess urinary acid equivalents.” Although we did not have the necessary data to conduct comprehensive analyses on acid-base status, we presented sufficient data to suggest that this mechanism is unlikely to explain the association between higher adiposity and higher FGF23 levels. First, we did not observe antiphosphaturic effects with higher adiposity; rather, as mentioned earlier, with every metric of higher adiposity we used, there was a greater urinary excretion of phosphate. Second, we specifically selected a population with normal kidney function; participants with estimated glomerular filtration rates of <60 mL/min/1.73 m2 were excluded from our analyses, and the mean glomerular filtration rate across quartiles of adiposity was comparable and >80 mL/min/1.73 m2. Thus, the assertion that impaired acid/base balance resulting in decreased phosphaturia could explain the higher FGF23 with higher adiposity in our study is the exact opposite of what we report: higher adiposity was associated with greater FGF23 and higher urinary excretion of phosphate, despite lower serum phosphate and normal kidney function. Ultimately, it must be restated that our study was observational and cross-sectional and not designed to determine the mechanism underlying our main finding. Although we postulated a potentially novel regulation of FGF23 in states of higher adiposity that appears to be independent of its conventional physiologic regulators (such as phosphate balance, vitamin D metabolism, and kidney function), more investigation will be needed to disentangle the mechanisms that contribute to this observation. Abbreviations: FGF23 fibroblast growth factor 23. Reference 1. Zaheer S, de Boer IH, Allison M, Brown JM, Psaty BM, Robinson-Cohen C, Michos ED, Ix JH, Kestenbaum B, Siscovick D, Vaidya A. Fibroblast growth factor 23, mineral metabolism, and adiposity in normal kidney function. J Clin Endocrinol Metab . 2017; 102( 4): 1387– 1395. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society

Journal

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Jan 1, 2018

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