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Fibroblast growth factor 23 is not associated with and does not induce arterial calcification.

Scialla JJ, Lau WL, Reilly MP, Isakova T, Yang HY, Crouthamel MH, Chavkin NW, Rahman M, Wahl P, Amaral AP, Hamano T, Master SR, Nessel L, Chai B, Xie D, Kallem RR, Chen J, Lash JP, Kusek JW, Budoff MJ, Giachelli CM, Wolf M, Chronic Renal Insufficiency Cohort Study Investigato - Kidney Int. (2013)

Bottom Line: Neither FGF23 nor serum phosphate were consistently associated with thoracic aorta calcium.Whereas elevated phosphate concentrations induced calcification in vitro, FGF23 had no effect on phosphate uptake or phosphate-induced calcification regardless of phosphate concentration or even in the presence of soluble klotho.Thus, in contrast to serum phosphate, FGF23 is not associated with arterial calcification and does not promote calcification experimentally.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.

ABSTRACT
Elevated fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease. As a potential mediating mechanism, FGF23 induces left ventricular hypertrophy; however, its role in arterial calcification is less clear. In order to study this, we quantified coronary artery and thoracic aorta calcium by computed tomography in 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC) study within a median of 376 days (interquartile range 331-420 days) of baseline. Baseline plasma FGF23 was not associated with the prevalence or severity of coronary artery calcium after multivariable adjustment. In contrast, higher serum phosphate levels were associated with prevalence and severity of coronary artery calcium, even after adjustment for FGF23. Neither FGF23 nor serum phosphate were consistently associated with thoracic aorta calcium. We could not detect mRNA expression of FGF23 or its coreceptor, klotho, in human or mouse vascular smooth muscle cells, or normal or calcified mouse aorta. Whereas elevated phosphate concentrations induced calcification in vitro, FGF23 had no effect on phosphate uptake or phosphate-induced calcification regardless of phosphate concentration or even in the presence of soluble klotho. Thus, in contrast to serum phosphate, FGF23 is not associated with arterial calcification and does not promote calcification experimentally. Hence, phosphate and FGF23 promote cardiovascular disease through distinct mechanisms.

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Adjusted prevalence ratios (black squares) and 95% confidence intervals (vertical bars) of coronary artery calcium (CAC) score greater than threshold values of (A) >0; (B) >100; (C) >400; and (D) >800. Results are presented by quartiles of plasma fibroblast growth factor 23 (FGF23) and serum phosphate with quartile 1 serving as the reference group. All models are adjusted for age, sex, race, ethnicity, eGFR, urine albumin-to-creatinine ratio, prior cardiovascular disease, diabetes, smoking, hypertension, hypercholesterolemia, body mass index, parathyroid hormone, corrected serum calcium, and clinical center. Models of FGF23 were additionally adjusted for serum phosphate. Models of serum phosphate were additionally adjusted for FGF23. P-values represent tests of trend across quartiles.
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Figure 2: Adjusted prevalence ratios (black squares) and 95% confidence intervals (vertical bars) of coronary artery calcium (CAC) score greater than threshold values of (A) >0; (B) >100; (C) >400; and (D) >800. Results are presented by quartiles of plasma fibroblast growth factor 23 (FGF23) and serum phosphate with quartile 1 serving as the reference group. All models are adjusted for age, sex, race, ethnicity, eGFR, urine albumin-to-creatinine ratio, prior cardiovascular disease, diabetes, smoking, hypertension, hypercholesterolemia, body mass index, parathyroid hormone, corrected serum calcium, and clinical center. Models of FGF23 were additionally adjusted for serum phosphate. Models of serum phosphate were additionally adjusted for FGF23. P-values represent tests of trend across quartiles.

Mentions: To assess whether the results were robust to different modeling strategies, we fit multivariable-adjusted ordinal logistic regression models to evaluate the odds ratio of a one category (0; 1–100; 101–400; and >400) increase in CAC or TAC score. Consistent with the primary results, higher serum phosphate, but not FGF23, was associated with greater odds of being in a higher CAC category, and neither was associated with TAC using this approach (Table 3). Finally, we modeled prevalence of CAC using alternate threshold values. Similar to prevalence of CAC >0 (Table 2; Figure 2a), higher quartiles of serum phosphate, but not plasma FGF23, were associated with greater prevalence of CAC scores above versus below 100, 400 and 800 in fully adjusted models (Figures 2b–d). Unlike TAC >0 (Table 2), higher quartiles of FGF23 were associated with greater prevalence of TAC >100, 400 and 800 but the estimates of effect were highly unstable and inconsistent across the different cut points (Supplemental Figure).


Fibroblast growth factor 23 is not associated with and does not induce arterial calcification.

Scialla JJ, Lau WL, Reilly MP, Isakova T, Yang HY, Crouthamel MH, Chavkin NW, Rahman M, Wahl P, Amaral AP, Hamano T, Master SR, Nessel L, Chai B, Xie D, Kallem RR, Chen J, Lash JP, Kusek JW, Budoff MJ, Giachelli CM, Wolf M, Chronic Renal Insufficiency Cohort Study Investigato - Kidney Int. (2013)

Adjusted prevalence ratios (black squares) and 95% confidence intervals (vertical bars) of coronary artery calcium (CAC) score greater than threshold values of (A) >0; (B) >100; (C) >400; and (D) >800. Results are presented by quartiles of plasma fibroblast growth factor 23 (FGF23) and serum phosphate with quartile 1 serving as the reference group. All models are adjusted for age, sex, race, ethnicity, eGFR, urine albumin-to-creatinine ratio, prior cardiovascular disease, diabetes, smoking, hypertension, hypercholesterolemia, body mass index, parathyroid hormone, corrected serum calcium, and clinical center. Models of FGF23 were additionally adjusted for serum phosphate. Models of serum phosphate were additionally adjusted for FGF23. P-values represent tests of trend across quartiles.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672330&req=5

Figure 2: Adjusted prevalence ratios (black squares) and 95% confidence intervals (vertical bars) of coronary artery calcium (CAC) score greater than threshold values of (A) >0; (B) >100; (C) >400; and (D) >800. Results are presented by quartiles of plasma fibroblast growth factor 23 (FGF23) and serum phosphate with quartile 1 serving as the reference group. All models are adjusted for age, sex, race, ethnicity, eGFR, urine albumin-to-creatinine ratio, prior cardiovascular disease, diabetes, smoking, hypertension, hypercholesterolemia, body mass index, parathyroid hormone, corrected serum calcium, and clinical center. Models of FGF23 were additionally adjusted for serum phosphate. Models of serum phosphate were additionally adjusted for FGF23. P-values represent tests of trend across quartiles.
Mentions: To assess whether the results were robust to different modeling strategies, we fit multivariable-adjusted ordinal logistic regression models to evaluate the odds ratio of a one category (0; 1–100; 101–400; and >400) increase in CAC or TAC score. Consistent with the primary results, higher serum phosphate, but not FGF23, was associated with greater odds of being in a higher CAC category, and neither was associated with TAC using this approach (Table 3). Finally, we modeled prevalence of CAC using alternate threshold values. Similar to prevalence of CAC >0 (Table 2; Figure 2a), higher quartiles of serum phosphate, but not plasma FGF23, were associated with greater prevalence of CAC scores above versus below 100, 400 and 800 in fully adjusted models (Figures 2b–d). Unlike TAC >0 (Table 2), higher quartiles of FGF23 were associated with greater prevalence of TAC >100, 400 and 800 but the estimates of effect were highly unstable and inconsistent across the different cut points (Supplemental Figure).

Bottom Line: Neither FGF23 nor serum phosphate were consistently associated with thoracic aorta calcium.Whereas elevated phosphate concentrations induced calcification in vitro, FGF23 had no effect on phosphate uptake or phosphate-induced calcification regardless of phosphate concentration or even in the presence of soluble klotho.Thus, in contrast to serum phosphate, FGF23 is not associated with arterial calcification and does not promote calcification experimentally.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.

ABSTRACT
Elevated fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease. As a potential mediating mechanism, FGF23 induces left ventricular hypertrophy; however, its role in arterial calcification is less clear. In order to study this, we quantified coronary artery and thoracic aorta calcium by computed tomography in 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC) study within a median of 376 days (interquartile range 331-420 days) of baseline. Baseline plasma FGF23 was not associated with the prevalence or severity of coronary artery calcium after multivariable adjustment. In contrast, higher serum phosphate levels were associated with prevalence and severity of coronary artery calcium, even after adjustment for FGF23. Neither FGF23 nor serum phosphate were consistently associated with thoracic aorta calcium. We could not detect mRNA expression of FGF23 or its coreceptor, klotho, in human or mouse vascular smooth muscle cells, or normal or calcified mouse aorta. Whereas elevated phosphate concentrations induced calcification in vitro, FGF23 had no effect on phosphate uptake or phosphate-induced calcification regardless of phosphate concentration or even in the presence of soluble klotho. Thus, in contrast to serum phosphate, FGF23 is not associated with arterial calcification and does not promote calcification experimentally. Hence, phosphate and FGF23 promote cardiovascular disease through distinct mechanisms.

Show MeSH
Related in: MedlinePlus