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

Letter to the Editor: “Fibroblast Growth Factor 23, Mineral Metabolism, and Adiposity in Normal... In a large cross-sectional study in adults with normal kidney function, Zaheer et al. (1) observed a significant positive relationship between serum concentrations of the bone-derived hyperphosphaturic hormone fibroblast growth factor 23 (FGF23) and different markers of adiposity. Unfortunately, the most probable metabolic cause for this observation, namely an increase in circulating insulin, regularly accompanying adiposity and insulin resistance, has not been considered by the authors. During usual insulin resistance, insulin receptor action remains widely preserved in parts of the kidney (2). Accordingly, as an antiphosphaturic hormone, insulin can directly induce proximal tubular phosphate transporters (2, 3), with the result that renal phosphate reabsorption is basically promoted in obesity and, in turn, higher FGF23 production is required to compensate for rising plasma phosphate. Additionally, another early consequence of adiposity is an incipient kidney function impairment frequently going along with increased urinary acidity, that is, lower 24-hour urine pH levels (4, 5). In this regard, in vitro studies using mouse bone organ cultures and primary osteoblasts have demonstrated a stimulation of FGF23 under acidosis conditions (6). Actually, renal phosphate excretion significantly increases and hypophosphatemia occurs in healthy humans under high acid loading and high net acid excretion (7, 8). This might be interpreted as a consequence of an acidosis-stimulated FGF23 elevation. Such an FGF23 stimulation, however, has not been shown in vivo. Only one intervention study has examined the responses of serum and urinary phosphate together with that of FGF23 after the induction of metabolic acidosis in healthy subjects with intact kidney function (8). Unexpectedly, this intervention shows that during strong acid loading not only renal phosphate excretion rises and plasma phosphate drops, but FGF23 drops as well (8). In accord herewith are recent results of a pilot study in patients with chronic kidney disease and mild metabolic acidosis demonstrating an increase in FGF23 after alkalization with sodium bicarbonate (9). In the literature, the acidity-induced augmentation of phosphaturia is discussed to be a direct kidney response aiming at efficiently enhancing the buffering and elimination of excess protons as titratable acidity. Owing to correspondingly lowered plasma phosphate in this condition, less hypophosphatemic FGF23 needs obviously to be secreted. Physiology experiments performed decades ago in anesthetized dogs have proven that an acidotic stimulus (acute increase of endogenous acetoacetate and hydroxybutyrate) during an alkalized state promptly induces a fall in plasma phosphate within minutes (10). In contrast, FGF23 responses to intravenous or duodenal phosphate loading are only seen after several hours. Hence, the direct acidosis (low-pH) stimulus on the kidney with its rapid inhibition of tubular phosphate reabsorption should clearly lower the need for an extra endocrine phosphaturic signal. Thus, it becomes understandable that higher alkali ingestion, requiring less renal buffering, results in an endocrine-responsive FGF23 increase to keep raising serum phosphate in limits. Taken together, changes in FGF23 may be compensatory (secondary) to changes in circulating phosphate, for example, with FGF23 increases boosted either by antiphosphaturic insulin elevations in obesity or by antiphosphaturic reductions in the necessity for buffering excess urinary acid equivalents. Accordingly, as long as kidney function is mostly normal, an increase in FGF23 can, but need not necessarily, be an indicator for an unfavorable metabolic status. Abbreviations: FGF23 fibroblast growth factor 23. References 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  2. Garland JS, Holden RM, Ross R, Adams MA, Nolan RL, Hopman WM, Morton AR. Insulin resistance is associated with fibroblast growth factor-23 in stage 3–5 chronic kidney disease patients. J Diabetes Complications . 2014; 28( 1): 61– 65. Google Scholar CrossRef Search ADS PubMed  3. Murer H, Hernando N, Forster I, Biber J. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol Rev . 2000; 80( 4): 1373– 1409. Google Scholar CrossRef Search ADS PubMed  4. Remer T, Berkemeyer S, Rylander R, Vormann J. Muscularity and adiposity in addition to net acid excretion as predictors of 24-h urinary pH in young adults and elderly. Eur J Clin Nutr . 2007; 61( 5): 605– 609. Google Scholar CrossRef Search ADS PubMed  5. Cho YH, Lee SY, Jeong DW, Choi EJ, Nam KJ, Kim YJ, Lee JG, Yi YH, Tak YJ, Cho BM, Lee SB, Lee KY. The association between a low urine pH and the components of metabolic syndrome in the Korean population: findings based on the 2010 Korea National health and nutrition examination survey. J Res Med Sci . 2014; 19( 7): 599– 604. Google Scholar PubMed  6. Krieger NS, Bushinsky DA. Stimulation of fibroblast growth factor 23 by metabolic acidosis requires osteoblastic intracellular calcium signaling and prostaglandin synthesis. Am J Physiol Renal Physiol . 2017; 313( 4): F882– F886. Google Scholar CrossRef Search ADS PubMed  7. Krapf R, Vetsch R, Vetsch W, Hulter HN. Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia. J Clin Invest . 1992; 90( 6): 2456– 2463. Google Scholar CrossRef Search ADS PubMed  8. Domrongkitchaiporn S, Disthabanchong S, Cheawchanthanakij R, Niticharoenpong K, Stitchantrakul W, Charoenphandhu N, Krishnamra N. Oral phosphate supplementation corrects hypophosphatemia and normalizes plasma FGF23 and 25-hydroxyvitamin D3 levels in women with chronic metabolic acidosis. Exp Clin Endocrinol Diabetes . 2010; 118( 2): 105– 112. Google Scholar CrossRef Search ADS PubMed  9. Chen W, Melamed ML, Hostetter TH, Bauer C, Raff AC, Almudevar AL, Lalonde A, Messing S, Abramowitz MK. Effect of oral sodium bicarbonate on fibroblast growth factor-23 in patients with chronic kidney disease: a pilot study. BMC Nephrol . 2016; 17( 1): 114. Google Scholar CrossRef Search ADS PubMed  10. Wathen RL, Ward RA, Harding GB, Meyer LC. Acid-base and metabolic responses to anion infusion in the anesthetized dog. Kidney Int . 1982; 21( 4): 592– 599. 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

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.2017-01806
Publisher site
See Article on Publisher Site

Abstract

In a large cross-sectional study in adults with normal kidney function, Zaheer et al. (1) observed a significant positive relationship between serum concentrations of the bone-derived hyperphosphaturic hormone fibroblast growth factor 23 (FGF23) and different markers of adiposity. Unfortunately, the most probable metabolic cause for this observation, namely an increase in circulating insulin, regularly accompanying adiposity and insulin resistance, has not been considered by the authors. During usual insulin resistance, insulin receptor action remains widely preserved in parts of the kidney (2). Accordingly, as an antiphosphaturic hormone, insulin can directly induce proximal tubular phosphate transporters (2, 3), with the result that renal phosphate reabsorption is basically promoted in obesity and, in turn, higher FGF23 production is required to compensate for rising plasma phosphate. Additionally, another early consequence of adiposity is an incipient kidney function impairment frequently going along with increased urinary acidity, that is, lower 24-hour urine pH levels (4, 5). In this regard, in vitro studies using mouse bone organ cultures and primary osteoblasts have demonstrated a stimulation of FGF23 under acidosis conditions (6). Actually, renal phosphate excretion significantly increases and hypophosphatemia occurs in healthy humans under high acid loading and high net acid excretion (7, 8). This might be interpreted as a consequence of an acidosis-stimulated FGF23 elevation. Such an FGF23 stimulation, however, has not been shown in vivo. Only one intervention study has examined the responses of serum and urinary phosphate together with that of FGF23 after the induction of metabolic acidosis in healthy subjects with intact kidney function (8). Unexpectedly, this intervention shows that during strong acid loading not only renal phosphate excretion rises and plasma phosphate drops, but FGF23 drops as well (8). In accord herewith are recent results of a pilot study in patients with chronic kidney disease and mild metabolic acidosis demonstrating an increase in FGF23 after alkalization with sodium bicarbonate (9). In the literature, the acidity-induced augmentation of phosphaturia is discussed to be a direct kidney response aiming at efficiently enhancing the buffering and elimination of excess protons as titratable acidity. Owing to correspondingly lowered plasma phosphate in this condition, less hypophosphatemic FGF23 needs obviously to be secreted. Physiology experiments performed decades ago in anesthetized dogs have proven that an acidotic stimulus (acute increase of endogenous acetoacetate and hydroxybutyrate) during an alkalized state promptly induces a fall in plasma phosphate within minutes (10). In contrast, FGF23 responses to intravenous or duodenal phosphate loading are only seen after several hours. Hence, the direct acidosis (low-pH) stimulus on the kidney with its rapid inhibition of tubular phosphate reabsorption should clearly lower the need for an extra endocrine phosphaturic signal. Thus, it becomes understandable that higher alkali ingestion, requiring less renal buffering, results in an endocrine-responsive FGF23 increase to keep raising serum phosphate in limits. Taken together, changes in FGF23 may be compensatory (secondary) to changes in circulating phosphate, for example, with FGF23 increases boosted either by antiphosphaturic insulin elevations in obesity or by antiphosphaturic reductions in the necessity for buffering excess urinary acid equivalents. Accordingly, as long as kidney function is mostly normal, an increase in FGF23 can, but need not necessarily, be an indicator for an unfavorable metabolic status. Abbreviations: FGF23 fibroblast growth factor 23. References 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  2. Garland JS, Holden RM, Ross R, Adams MA, Nolan RL, Hopman WM, Morton AR. Insulin resistance is associated with fibroblast growth factor-23 in stage 3–5 chronic kidney disease patients. J Diabetes Complications . 2014; 28( 1): 61– 65. Google Scholar CrossRef Search ADS PubMed  3. Murer H, Hernando N, Forster I, Biber J. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol Rev . 2000; 80( 4): 1373– 1409. Google Scholar CrossRef Search ADS PubMed  4. Remer T, Berkemeyer S, Rylander R, Vormann J. Muscularity and adiposity in addition to net acid excretion as predictors of 24-h urinary pH in young adults and elderly. Eur J Clin Nutr . 2007; 61( 5): 605– 609. Google Scholar CrossRef Search ADS PubMed  5. Cho YH, Lee SY, Jeong DW, Choi EJ, Nam KJ, Kim YJ, Lee JG, Yi YH, Tak YJ, Cho BM, Lee SB, Lee KY. The association between a low urine pH and the components of metabolic syndrome in the Korean population: findings based on the 2010 Korea National health and nutrition examination survey. J Res Med Sci . 2014; 19( 7): 599– 604. Google Scholar PubMed  6. Krieger NS, Bushinsky DA. Stimulation of fibroblast growth factor 23 by metabolic acidosis requires osteoblastic intracellular calcium signaling and prostaglandin synthesis. Am J Physiol Renal Physiol . 2017; 313( 4): F882– F886. Google Scholar CrossRef Search ADS PubMed  7. Krapf R, Vetsch R, Vetsch W, Hulter HN. Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia. J Clin Invest . 1992; 90( 6): 2456– 2463. Google Scholar CrossRef Search ADS PubMed  8. Domrongkitchaiporn S, Disthabanchong S, Cheawchanthanakij R, Niticharoenpong K, Stitchantrakul W, Charoenphandhu N, Krishnamra N. Oral phosphate supplementation corrects hypophosphatemia and normalizes plasma FGF23 and 25-hydroxyvitamin D3 levels in women with chronic metabolic acidosis. Exp Clin Endocrinol Diabetes . 2010; 118( 2): 105– 112. Google Scholar CrossRef Search ADS PubMed  9. Chen W, Melamed ML, Hostetter TH, Bauer C, Raff AC, Almudevar AL, Lalonde A, Messing S, Abramowitz MK. Effect of oral sodium bicarbonate on fibroblast growth factor-23 in patients with chronic kidney disease: a pilot study. BMC Nephrol . 2016; 17( 1): 114. Google Scholar CrossRef Search ADS PubMed  10. Wathen RL, Ward RA, Harding GB, Meyer LC. Acid-base and metabolic responses to anion infusion in the anesthetized dog. Kidney Int . 1982; 21( 4): 592– 599. 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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